Aryl aniline beta2 adrenergic receptor agonists

ABSTRACT

The invention provides novel β 2  adrenergic receptor agonist compounds of formula (I):  
                 
 
     wherein R 1 -R 13  and w have any of the values described in the specification. The invention also provides combinations of such compounds and other therapeutic agents, pharmaceutical compositions comprising such compounds and combinations, methods of using such compounds to treat diseases associated with β 2  adrenergic receptor activity, and processes and intermediates useful for preparing such compounds.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation-in-part of U.S. applicationSer. No. 10/292,835, filed Nov. 12, 2002, which claims the benefit ofU.S. Provisional Application No. 60/338,194, filed Nov. 13, 2001 andU.S. Provisional Application No. 60/343,771, filed Dec. 28, 2001, theentire disclosures of which are incorporated herein by reference.

FIELD OF THE INVENTION

[0002] The invention is directed to novel β₂ adrenergic receptoragonists. The invention is also directed to pharmaceutical compositionscomprising such compounds, methods of using such compounds to treatdiseases associated with β₂ adrenergic receptor activity, and processesand intermediates useful for preparing such compounds.

BACKGROUND OF THE INVENTION

[0003] β₂ adrenergic receptor agonists are recognized as effective drugsfor the treatment of pulmonary diseases such as asthma and chronicobstructive pulmonary disease (including chronic bronchitis andemphysema). β₂ adrenergic receptor agonists are also useful for treatingpre-term labor, and are potentially useful for treating neurologicaldisorders and cardiac disorders. In spite of the success that has beenachieved with certain β₂ adrenergic receptor agonists, current agentspossess less than desirable potency, selectivity, speed of onset, and/orduration of action. Thus, there is a need for additional β₂ adrenergicreceptor agonists having improved properties. Preferred agents maypossess, among other properties, improved duration of action, potency,selectivity, and/or onset.

SUMMARY OF THE INVENTION

[0004] The invention provides novel compounds that possess β₂ adrenergicreceptor agonist activity. Accordingly, this invention providescompounds of formula (I):

[0005] wherein:

[0006] each of R₁-R⁵ is independently selected from the group consistingof hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl,heterocyclyl, and R^(a);

[0007] or R¹ and R², R² and R³, R³ and R⁴, or R⁴ and R⁵ are joinedtogether to form a group selected from the group consisting of—C(R^(d))═C(R^(d))C(═O)NR^(d)—, —CR^(d)R^(d)—CR^(d)R^(d)—C(═O)NR^(d)—,—NR^(d)C(═O)C(R^(d))═C(R^(d))—, —NR^(d)C(═O)CR^(d)R^(d)—CR^(d)R^(d)—,—NR^(d)C(═O)S—, —SC(═O)NR^(d)—, —(CR^(d)R^(d))_(p)—,—S(CR^(d)R^(d))_(q)—, —(CR^(d)R^(d))_(q)S—, —S(CR^(d)R^(d))_(r)O—,—O(CR^(d)R^(d))_(r)S—, and —NHC(R^(j))═C(R^(k))—;

[0008] R⁶ is hydrogen, alkyl, or alkoxy;

[0009] R⁷ is hydrogen or alkyl;

[0010] R⁸ is hydrogen or alkyl; or R⁸ together with R⁹ is —CH₂— or—CH₂CH₂—;

[0011] R⁹ is independently selected from the group consisting of alkyl,alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, and R^(a),or R⁹ together with R⁸ is —CH₂— or —CH₂CH₂—;

[0012] R¹⁰ is hydrogen or alkyl;

[0013] each R¹¹, R¹², and R¹³ is independently selected from the groupconsisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl,heteroaryl, heterocyclyl, —NO₂, halo, —NR^(d)R^(e), —C(═O)R^(d),—CO₂R^(d), —OC(═O)R^(d), —CN, —C(═O)NR^(d)R^(e), —NR^(d)C(═O)R^(e),—OC(═O)NR^(d)R^(e), —NR^(d)C(═O)OR^(e), —NR^(d)C(═O)NR^(d)R^(e),—OR^(d), S(O)_(m)R^(d), —NR^(d)—NR^(d)—C(═O)R^(d),—NR^(d)—N═CR^(d)R^(d), —N(NR^(d)R^(e))R^(d), and —S(O)₂NR^(d)R^(e);

[0014] or R¹¹ and R¹² together with the atoms to which they are attachedform a fused benzo ring, which benzo ring can optionally be substitutedwith 1, 2, 3, or 4 R_(c);

[0015] or R¹¹ and R¹² together with the atoms to which they are attachedform a heterocyclic ring;

[0016] wherein for R¹-R⁶, R⁹, and R¹¹-R¹³, each alkyl, alkenyl, andalkynyl is optionally substituted with R^(m), or with one or more (e.g.1, 2, 3, or 4) substituents independently selected from R^(b); forR¹-R⁶, R⁹, and R¹¹-R¹³ each aryl and heteroaryl is optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(c), and for R¹-R⁶, R⁹, and R¹¹-R¹³ each cycloalkyl and heterocyclicring is optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(b) and R^(c);

[0017] each R^(a) is independently —OR^(d), —NO₂, halo, —S(O)_(m)R^(d),—S(O)₂OR^(d), S(O)_(m)NR^(d)R^(e), —NR^(d)R^(e),O(CR_(f)R^(g))_(n)NR^(d)R^(e), —C(═O)R^(d), —CO₂R^(d),—CO₂(CR^(f)R^(g))_(n)CONR^(d)R^(e), —OC(═O)R^(d), —CN,—C(═O)NR^(d)R^(e), —NR^(d)C(═O)R^(e), —OC(═O)NR^(d)R^(e),—NR^(d)C(═O)OR^(e), —NR^(d)C(═O)NR^(d)R^(e), —CR^(d)(═N—OR^(e)), —CF₃,or —OCF₃;

[0018] each R^(b) is independently R^(a), oxo, or ═N—OR^(e);

[0019] each R^(c) is independently R^(a), alkyl, alkenyl, or alkynyl;wherein each alkyl, alkenyl and alkynyl is optionally substituted with1, 2, 3, or 4 substituents independently selected from R^(b);

[0020] each R^(d) and R^(e) is independently hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; wherein eachalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocyclylis optionally substituted with one or more (e.g. 1, 2, 3, or 4)substituents independently selected from R^(h); or R^(d) and R^(e)together with the atoms to which they are attached form a heterocyclicring having from 5 to 7 ring atoms, wherein the heterocyclic ringoptionally contains 1 or 2 additional heteroatoms independently selectedfrom oxygen, sulfur and nitrogen;

[0021] each R^(f) and R^(g) is independently hydrogen, alkyl, aryl,heteroaryl, cycloalkyl, or heterocyclyl; wherein each alkyl, aryl,heteroaryl, cycloalkyl and heterocyclyl is optionally substituted with1, 2, 3, or 4 substituents independently selected from R^(h); or R^(f)and R^(g) together with the carbon atom to which they are attached forma ring having from 5 to 7 ring atoms, wherein the ring optionallycontains 1 or 2 heteroatoms independently selected from oxygen, sulfurand nitrogen;

[0022] each R^(h) is independently halo, C₁₋₈alkyl, C₁₋₈alkoxy,—S—C₁₋₈alkyl, aryl, (aryl)-C₁₋₆alkyl, (aryl)-C₁₋₈alkoxy, heteroaryl,(heteroaryl)-C₁₋₆alkyl, (heteroaryl)-C₁₋₈alkoxy, hydroxy, amino,—NHC₁₋₆alkyl, —N(C₁₋₆alkyl)₂, —OC(═O)C₁₋₆alkyl, —C(═O)C₁₋₆alkyl,—C(═O)OC₁₋₆alkyl, —NHC(═O)C₁₋₆alkyl, —C(═O)NHC₁₋₆alkyl, carboxy, nitro,—CN, or —CF₃;

[0023] R^(j) and R^(k) together with the carbon atoms to which they areattached form a phenyl ring that is optionally substituted with 1, 2, 3,or 4 R^(c);

[0024] each R^(m) is independently aryl, heteroaryl, cycloalkyl orheterocyclyl; wherein each aryl or heteroaryl is optionally substitutedwith 1, 2, 3, or 4 substituents selected from the group consisting ofR^(c), and wherein each cycloalkyl and heterocyclyl is optionallysubstituted with 1, 2, 3, or 4 substituents selected from R^(b);

[0025] m is 0, 1, or 2;

[0026] n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0027] p is 3, 4, or 5;

[0028] q is 2, 3, or 4;

[0029] r is 1,2, or 3;

[0030] w is 0, 1, 2, 3, or 4;

[0031] or a pharmaceutically-acceptable salt or solvate or stereoisomerthereof.

[0032] The invention also provides compounds of formula (IIa):

[0033] wherein:

[0034] R⁴ is —CH₂OH or —NHCHO and R⁵ is hydrogen; or R⁴ and R⁵ takentogether are —NHC(═O)CH═CH—;

[0035] R¹¹ is phenyl or heteroaryl, wherein each phenyl is optionallysubstituted with 1 or 2 substituents selected from halo, —OR^(d), —CN,—NO₂, —SO₂R^(d), —C(═O)R^(d), C(═O)NR^(d)R^(e), and C₁₋₃alkyl, whereinC₁₋₃alkyl is optionally substituted with 1 or 2 substituents selectedfrom carboxy, hydroxy, and amino, and each R^(d) and R^(e) isindependently hydrogen or C₁₋₃alkyl; and wherein each heteroaryl isoptionally substituted with 1 or 2 C₁₋₃alkyl substituents; and

[0036] R¹² is hydrogen or —OC₁₋₆alkyl;

[0037] or a pharmaceutically-acceptable salt or solvate or stereoisomerthereof.

[0038] The invention also provides compounds of formula (IIb):

[0039] wherein:

[0040] R⁴ is —CH₂OH or —NHCHO and R⁵ is hydrogen; or R⁴ and R⁵ takentogether are —NHC(═O)CH═CH—;

[0041] R¹² is hydrogen or —OC₁₋₆alkyl;

[0042] R¹⁷ is —(CH₂)_(x)NR^(d)R^(e) wherein each R^(d) and R^(e) isindependently hydrogen or C₁₋₄alkyl, wherein each C₁₋₄alkyl isoptionally substituted with phenyl or pyridyl, or R^(d) and R^(e)together with the nitrogen atom to which they are attached ismorpholino; and

[0043] x is 0, 1, or 2.

[0044] The invention also provides a pharmaceutical compositioncomprising a compound of the invention and a pharmaceutically-acceptablecarrier. The invention further provides combinations comprising acompound of the invention and one or more other therapeutic agents andpharmaceutical compositions comprising such combinations.

[0045] The invention also provides a method of treating a disease orcondition associated with β₂ adrenergic receptor activity (e.g. apulmonary disease, such as asthma or chronic obstructive pulmonarydisease, pre-term labor, a neurological disorder, a cardiac disorder, orinflammation) in a mammal, comprising administering to the mammal, atherapeutically effective amount of a compound of the invention. Theinvention further provides a method of treatment comprisingadministering a therapeutically effective amount of a combination of acompound of the invention together with one or more other therapeuticagents.

[0046] The invention also provides a method of treating a disease orcondition associated with β₂ adrenergic receptor activity (e.g. apulmonary disease, such as asthma or chronic obstructive pulmonarydisease, pre-term labor, a neurological disorder, a cardiac disorder, orinflammation) in a mammal, comprising administering to the mammal, atherapeutically effective amount of a pharmaceutical composition of theinvention.

[0047] This invention also provides a method of modulating a β₂adrenergic receptor, the method comprising stimulating a β₂ adrenergicreceptor with a modulatory amount of a compound of the invention.

[0048] In separate and distinct aspects, the invention also providessynthetic processes and novel intermediates, including compounds offormulas (III), (IV), and (VII) described herein, which are useful forpreparing compounds of the invention.

[0049] The invention also provides a compound of the invention asdescribed herein for use in medical therapy, as well as the use of acompound of the invention in the manufacture of a formulation ormedicament for treating a disease or condition associated with β₂adrenergic receptor activity (e.g. a pulmonary disease, such as asthmaor chronic obstructive pulmonary disease, pre-term labor, a neurologicaldisorder, a cardiac disorder, or inflammation) in a mammal.

DETAILED DESCRIPTION OF THE INVENTION

[0050] When describing the compounds, compositions and methods of theinvention, the following terms have the following meanings, unlessotherwise indicated.

[0051] The term “alkyl” refers to a monovalent saturated hydrocarbongroup which may be linear or branched or combinations thereof. Suchalkyl groups preferably contain from 1 to 20 carbon atoms; morepreferably, from 1 to 8 carbon atoms; and still more preferably, from 1to 4 carbon atoms. Representative alkyl groups include, by way ofexample, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl,n-decyl and the like.

[0052] The term “alkenyl” refers to a monovalent unsaturated hydrocarbongroup containing at least one carbon-carbon double bond, typically 1 or2 carbon-carbon double bonds, and which may be linear or branched orcombinations thereof. Such alkenyl groups preferably contain from 2 to20 carbon atoms; more preferably from 2 to 8 carbon atoms; and stillmore preferably, from 2 to 4 carbon atoms. Representative alkenyl groupsinclude, by way of example, vinyl, allyl, isopropenyl, but-2-enyl,n-pent-2-enyl, n-hex-2-enyl, n-hept-2-enyl, n-oct-2-enyl, n-non-2-enyl,n-dec-4-enyl, n-dec-2,4-dienyl and the like.

[0053] The term “alkynyl” refers to a monovalent unsaturated hydrocarbongroup containing at least one carbon-carbon triple bond, typically 1carbon-carbon triple bond, and which may be linear or branched orcombinations thereof. Such alkynyl groups preferably contain from 2 to20 carbon atoms; more preferably from 2 to 8 carbon atoms; and stillmore preferably, from 2 to 4 carbon atoms. Representative alkynyl groupsinclude, by way of example, ethynyl, propargyl, but-2-ynyl and the like.

[0054] The term “alkoxy” refers to a group of the formula —OR, where Ris an alkyl group as defined herein. Representative alkoxy groupsinclude, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, n-pentoxy, n-hexoxy andthe like.

[0055] The term “cycloalkyl” refers to a monovalent saturatedcarbocyclic group which may be monocyclic or multicyclic. Each ring ofsuch cycloalkyl groups preferably contains from 3 to 10 carbon atoms.This term also includes cycloalkyl groups fused to an aryl or heteroarylgroup in which the point of attachment is on the non-aromatic(cycloalkyl) portion of the group. Representative cycloalkyl groupsinclude, by way of example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, 1,2,3,4-tetrahydronaphth-2-yl,decahydronaphthyl, indan-1-yl, adamantyl, norbornyl and the like.

[0056] The term “aryl” refers to a monovalent carbocyclic group whichmay be monocyclic or multicyclic (i.e., fused) wherein at least one ringis aromatic. Such aryl groups preferably contain from 6 to 20 carbonatoms; more preferably, from 6 to 10 carbon atoms. This term includesmulticyclic carbocyclic ring systems wherein one or more rings are notaromatic, provided the point of attachment is on an aromatic ring.Representative aryl groups include, by way of example, phenyl, napthyl,azulenyl, indan-5-yl, 1,2,3,4-tetrahydronaphth-6-yl, and the like.

[0057] The term “heteroaryl” refers to a monovalent aromatic group thatcontains at least one heteroatom, preferably 1 to 4 heteroatoms,selected from N, S and O, and which may be monocyclic or multicyclic(i.e., fused). Such heteroaryl groups preferably contain from 5 to 20atoms; more preferably, from 5 to 10 atoms. This term also includesheteroaryl groups fused to a cycloalkyl or aryl group, in which thepoint of attachment is on the aromatic (heteroaryl) portion of thegroup. Representative heteroaryl groups include, by way of example,pyrroyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl (or, equivalently,pyridinyl), oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl,triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl,pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl,benzofuranyl, benzothiophenyl, quinolyl, indolyl, isoquinolyl and thelike.

[0058] The term “heterocyclyl” or “heterocyclic ring” refers to asaturated or partially unsaturated cyclic non-aromatic group, which maybe monocyclic or multicyclic (i.e., fused or bridged), and whichcontains at least one heteroatom, preferably 1 to 4 heteroatoms,selected from N(X), S and O, wherein each X is independently hydrogen oralkyl. Such heterocyclyl groups preferably contain from 3 to 20 atoms;more preferably, from 3 to 10 atoms. This term also includes such aheterocyclyl group fused to one or more cycloalkyl, aryl, or heteroarylgroups. The point of attachment of the heterocyclyl group may be anycarbon or nitrogen atom in a heterocyclyl, cycloalkyl, aryl orheteroaryl portion of the group. Representative heterocyclyl groupsinclude, by way of example, pyrrolidinyl, piperidinyl, piperazinyl,imidazolidinyl, morpholinyl, indolin-3-yl, 2-imidazolinyl,1,2,3,4-tetrahydroisoquinolin-2-yl, quinuclidinyl, 2-oxobenzopyran, andthe like.

[0059] The term “halo” refers to a fluoro, chloro, bromo or iodo.

[0060] The term “oxo” refers to a group of the formula ═O.

[0061] The term “therapeutically effective amount” refers to an amountsufficient to effect treatment when administered to a patient in need oftreatment.

[0062] The term “treatment” as used herein refers to the treatment of adisease or medical condition in a patient, such as a mammal(particularly a human), and includes:

[0063] (a) preventing the disease or medical condition from occurring,i.e., prophylactic treatment of a patient;

[0064] (b) ameliorating the disease or medical condition, i.e.,eliminating or causing regression of the disease or medical condition ina patient;

[0065] (c) suppressing the disease or medical condition, i.e., slowingor arresting the development of the disease or medical condition in apatient; or

[0066] (d) alleviating the symptoms of the disease or medical conditionin a patient.

[0067] The phrase “disease or condition associated with β₂ adrenergicreceptor activity” includes all disease states and/or conditions thatare acknowledged now, or that are found in the future, to be associatedwith β₂ adrenergic receptor activity. Such disease states include, butare not limited to, bronchoconstrictive or pulmonary diseases, such asasthma and chronic obstructive pulmonary disease (including chronicbronchitis and emphysema), as well as neurological disorders and cardiacdisorders. β₂ Adrenergic receptor activity is also known to beassociated with pre-term labor (see, for example, U.S. Pat. No.5,872,126) and some types of inflammation (see, for example, WO 99/30703and U.S. Pat. No. 5,290,815).

[0068] The term “pharmaceutically-acceptable salt” refers to a saltprepared from a base or acid which is acceptable for administration to apatient, such as a mammal. Such salts can be derived frompharmaceutically-acceptable inorganic or organic bases and frompharmaceutically-acceptable inorganic or organic acids.

[0069] Salts derived from pharmaceutically-acceptable acids includeacetic, benzenesulfonic, benzoic, camphosulfonic, citric,ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric,pantothenic, phosphoric, succinic, sulfuric, tartaric,p-toluenesulfonic, xinafoic (1-hydroxy-2-naphthoic acid) and the like.Particularly preferred are salts derived from fumaric, hydrobromic,hydrochloric, acetic, sulfuric, phosphoric, methanesulfonic,p-toluenesulfonic, xinafoic, tartaric, citric, malic, maleic, succinic,and benzoic acids.

[0070] Salts derived from pharmaceutically-acceptable inorganic basesinclude aluminum, ammonium, calcium, copper, ferric, ferrous, lithium,magnesium, manganic, manganous, potassium, sodium, zinc and the like.Particularly preferred are ammonium, calcium, magnesium, potassium andsodium salts. Salts derived from pharmaceutically-acceptable organicbases include salts of primary, secondary and tertiary amines, includingsubstituted amines, cyclic amines, naturally-occuring amines and thelike, such as arginine, betaine, caffeine, choline,N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lysine, methylglucamine, morpholine,piperazine, piperadine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylamine, tripropylamine, tromethamineand the like.

[0071] The term “solvate” refers to a complex or aggregate formed by oneor more molecules of a solute, i.e. a compound of the invention or apharmaceutically-acceptable salt thereof, and one or more molecules of asolvent. Such solvates are typically crystalline solids having asubstantially fixed molar ratio of solute and solvent. Representativesolvents include by way of example, water, methanol, ethanol,isopropanol, acetic acid, and the like. When the solvent is water, thesolvate formed is a hydrate.

[0072] The term “leaving group” refers to a functional group or atomwhich can be displaced by another functional group or atom in asubstitution reaction, such as a nucleophilic substitution reaction. Byway of example, representative leaving groups include chloro, bromo andiodo groups; sulfonic ester groups, such as mesylate, tosylate,brosylate, nosylate and the like; and acyloxy groups, such as acetoxy,trifluoroacetoxy and the like.

[0073] The term “amino-protecting group” refers to a protecting groupsuitable for preventing undesired reactions at an amino nitrogen.Representative amino-protecting groups include, but are not limited to,formyl; acyl groups, for example alkanoyl groups, such as acetyl;alkoxycarbonyl groups, such as tert-butoxycarbonyl (Boc);arylmethoxycarbonyl groups, such as benzyloxycarbonyl (Cbz) and9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl groups, such as benzyl(Bn), trityl (Tr), and 1,1-di-(4′-methoxyphenyl)methyl; silyl groups,such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS); and thelike.

[0074] The term “hydroxy-protecting group” refers to a protecting groupsuitable for preventing undesired reactions at a hydroxy group.Representative hydroxy-protecting groups include, but are not limitedto, alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups,for example alkanoyl groups, such as acetyl; arylmethyl groups, such asbenzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), anddiphenylmethyl (benzhydryl, DPM); silyl groups, such as trimethylsilyl(TMS) and tert-butyldimethylsilyl (TBS); and the like.

[0075] Specific and preferred values listed below for radicals,substituents, and ranges, are for illustration only; they do not excludeother defined values or other values within defined ranges for theradicals and substituents.

[0076] A specific value for R¹ is hydrogen.

[0077] A specific value for R² is hydrogen.

[0078] A specific value for R³ is hydroxy.

[0079] A specific value for R⁴ is —CH₂OH or —NHCHO.

[0080] A specific value for R⁵ is hydrogen.

[0081] A specific value for R⁴ and R⁵ together are —NHC(═O)CH═CH— or—SC(═O)NH—.

[0082] A specific value for R⁶ is hydrogen.

[0083] A specific value for R⁷ is hydrogen.

[0084] A specific value for R⁸ is hydrogen.

[0085] A specific value for w is 0.

[0086] Another specific value for w is 1 or 2.

[0087] A specific value for R⁹ together with R⁸ is —CH₂— or —CH₂CH₂—.

[0088] A specific value for R¹⁰ is hydrogen.

[0089] Another specific value for R¹⁰ is alkyl.

[0090] A specific value for R¹¹ is hydrogen.

[0091] Another specific value for R¹¹ is alkyl, alkenyl, alkynyl, aryl,heteroaryl, heterocyclyl, —NO₂, halo, —NR^(d)R^(e), —C(═O)R^(d),—CO₂R^(d), —OC(═O)R^(d), —CN, —C(═O)NR^(d)R^(e), —NR^(d)C(═O)R^(e),—OC(═O)NR^(d)R^(e), —NR^(d)C(═O)OR^(e), —NR^(d)C(═O)NR^(d)R^(e),—OR^(d), —S(O)_(m)R^(d), —NR^(d)—NR^(d)—C(═O)R^(d),—NR^(d)—N═CR^(d)R^(d), —N(NR^(d)R^(e))R^(d), or —S(O)₂NR^(d)R^(e).

[0092] Another specific value for R¹¹ is hydrogen, alkyl, heterocyclyl,—OR^(d), —S(O)_(m)R^(d), or —S(O)₂NR^(d)R^(e).

[0093] Another specific value for R¹¹ is heterocyclyl, —OR^(d),—S(O)_(m)R^(d), or —S(O)₂NR^(d)R^(e).

[0094] Another specific value for R¹¹ is —OR^(d).

[0095] Another specific value for R¹¹ is —S(O)_(m)R^(d).

[0096] A specific value for R¹² is hydrogen.

[0097] Another specific value for R¹² is alkyl, alkenyl, alkynyl, aryl,heteroaryl, heterocyclyl, —NO₂, halo, —NR^(d)R^(e), —C(═O)R^(d),—CO₂R^(d), —OC(═O)R^(d), —CN, —C(═O)NR^(d)R^(e), —NR^(d)C(═O)R^(e),—OC(═O)NR^(d)R^(e), —NR^(d)C(═O)OR^(e), —NR^(d)C(═O)NR^(d)R^(e),—OR^(d), —S(O)_(m)R^(d), —NR^(d)—NR^(d)—C(═O)R^(d),—NR^(d)—N═CR^(d)R^(d), —N(NR^(d)R^(e))R^(d), or S(O)₂NR^(d)R^(e).

[0098] Another specific value for R¹² is hydrogen, alkyl, heterocyclyl,—OR^(d), —S(O)_(m)R^(d), or —S(O)₂NR^(d)R^(e).

[0099] A specific value for R¹² is heterocyclyl, —OR^(d),—S(O)_(m)R^(d), or —S(O)₂NR^(d)R^(e).

[0100] Another specific value for R¹² is —OR^(d).

[0101] Another specific value for R¹² is —S(O)_(m)R^(d).

[0102] Another specific value for R¹² is —S(O)₂NR^(d)R^(e).

[0103] A specific value for R¹³ is hydrogen.

[0104] Another specific value for R¹³ is alkyl, alkenyl, alkynyl, aryl,heteroaryl, heterocyclyl, —NO₂, halo, —NR^(d)R^(e), —C(═O)R^(d),—CO₂R^(d), —OC(═O)R^(d), —CN, C(═O)NR^(d)R^(e), —NR^(d)C(═O)R^(e),—OC(═O)NR^(d)R^(e), —NR^(d)C(═O)OR^(e), —NR^(d)C(═O)NR^(d)R^(e),—OR^(d), —S(O)_(m)R^(d), —NR^(d)—NR^(d)—C(═O)R^(d),—NR^(d)—N═CR^(d)R^(d), —N(NR^(d)R^(e))R^(d), or S(O)₂NR^(d)R^(e).

[0105] Another specific value for R¹³ is hydrogen, alkyl, heterocyclyl,—OR^(d), S(O)_(m)R^(d), or —S(O)₂NR^(d)R^(e).

[0106] Another specific value for R¹³ is heterocyclyl, —OR^(d),—S(O)_(m)R^(d), or —S(O)₂NR^(d)R^(e).

[0107] A specific value for R¹³ is —OR^(d).

[0108] A specific value for R¹¹ is —S(O)_(m)R^(d).

[0109] A specific group of compounds of the invention are compoundswherein each of R¹-R⁴ is independently selected from the groupconsisting of hydrogen, fluoro, chloro, amino, hydroxy,N,N-dimethylaminocarbonyloxy, —CH₂OH, and —NHCHO, and R⁵ is hydrogen; orR¹ is hydrogen, R² is hydrogen, R³ is hydroxy, and R⁴ and R⁵ togetherare —NHC(═O)CH═CH— or —SC(═O)NH—.

[0110] A specific group of compounds of the invention are compoundswherein R¹ is hydrogen; R² is chloro; R³ is amino; R⁴ is chloro; and R⁵is hydrogen.

[0111] A specific group of compounds of the invention are compoundswherein R¹ is hydrogen; R² is N,N-dimethylaminocarbonyloxy; R³ ishydrogen; R⁴ is N,N-dimethylaminocarbonyloxy; and R⁵ is hydrogen.

[0112] A specific group of compounds of the invention are compoundswherein R¹ is hydrogen, fluoro, or chloro; R² is hydroxy; R³ ishydrogen; R⁴ is hydroxy; and R⁵ is hydrogen.

[0113] A specific group of compounds of the invention are compoundswherein R¹ is chloro; R² is hydrogen; R³ is hydroxy; R⁴ is hydrogen; andR⁵ is hydrogen.

[0114] A specific group of compounds of the invention are compoundswherein R is hydrogen; R² is hydrogen; R³ is hydroxy; R⁴ is —CH₂OH; andR⁵ is hydrogen.

[0115] A specific group of compounds of the invention are compoundswherein R¹ is hydrogen; R² is hydrogen; R³ is hydroxy; R⁴ is —NHCHO; andR⁵ is hydrogen.

[0116] A specific group of compounds of the invention are compoundswherein R¹ is hydrogen; R² is hydrogen; R³ is hydroxy; and R⁴ and R⁵together are —NHC(═O)CH═CH—.

[0117] A specific group of compounds of the invention are compoundswherein R¹ is hydrogen; R² is hydrogen; R³ is hydroxy; and R⁴ and R⁵together are —SC(═O)NH—.

[0118] A specific group of compounds of the invention are compoundswherein R¹¹ is hydrogen, R¹² is —SR^(d); R¹³ is hydrogen; and R^(d) isalkyl, aryl, or heteroaryl.

[0119] A specific group of compounds of the invention are compoundswherein R¹¹ is —SR^(d), R¹² is hydrogen; R¹³ is hydrogen; and R^(d) isalkyl, aryl, heteroaryl.

[0120] When part of the group —SR^(d), a specific value for R^(d) isalkyl.

[0121] When part of the group —SR^(d), another specific value for R^(d)is C₁₋₆alkyl.

[0122] When part of the group —SR^(d), another specific value for Rd isC₁₋₃alkyl.

[0123] When part of the group —SR^(d), another more specific value forR^(d) is aryl optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from halo, C₁₋₆alkyl, C₁₋₆alkoxy, hydroxy, amino,—N(C₁₋₆alkyl)₂, nitro, —CN, and —CF₃.

[0124] When part of the group —SR^(d), another more specific value forR^(d) is phenyl optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from fluoro and C₁₋₃alkyl.

[0125] A specific group of compounds of the invention are compoundswherein R¹¹ or R¹² is methylthio, 2-methylphenylthio,4-methyl-2-pyrimidylthio, 4-fluorophenylthio, or 4-methylphenylthio.

[0126] A specific group of compounds of the invention are compoundswherein R¹¹ is hydrogen or alkyl, R¹² is —SO₂NR^(d)R^(e); and R¹¹ ishydrogen.

[0127] A specific group of compounds of the invention are compoundswherein R¹¹ is —SO₂NR^(d)R^(e), R¹² is hydrogen or alkyl; and R¹¹ ishydrogen.

[0128] When part of the group —SO₂NR^(d)R^(e), a specific value forR^(d) is alkyl, aryl, or heteroaryl; and for R_(e) is hydrogen, alkyl,aryl, or heteroaryl; wherein each alkyl, aryl, or heteroaryl, isoptionally substituted with one or more (e.g. 1, 2, 3, or 4)substituents independently selected from R^(h); or R^(d) and R^(e)together with the nitrogen atom to which they are attached is aheterocyclic ring having from 5 to 7 ring atoms, wherein theheterocyclic ring optionally contains 1 or 2 additional heteroatomsindependently selected from oxygen, sulfur or nitrogen.

[0129] When part of the group —SO₂NR^(d)R^(e), a specific value forR^(d) and R^(e) independently is hydrogen, alkyl, aryl, or heteroaryl;wherein each alkyl, aryl, or heteroaryl, is optionally substituted with1, 2, 3, or 4 substituents independently selected from R^(h).

[0130] As a substituent as part of the group —SO₂NR^(d)R^(e), a specificvalue for R^(h) is halo, C₁₋₈alkyl, C₁₋₈alkoxy, —S—C₁₋₈alkyl, aryl,hydroxy, amino, —NHC₁₋₆alkyl, —N(C₁₋₆alkyl)₂, —OC(═O)C₁₋₆alkyl,—C(═O)C₁₋₆alkyl, —C(═O)OC₁₋₆alkyl, —NHC(═O)C₁₋₆alkyl, —C(═O)NHC₁₋₆alkyl,carboxy, nitro, —CN, or —CF₃.

[0131] Another specific value for R^(h) in the above context is halo,C₁₋₆alkyl, C₁₋₆alkoxy, or —CF₃.

[0132] When part of the group —SO₂NR^(d)R^(e), a specific value forR^(d) and R^(e) together with the nitrogen atom to which they areattached is a heterocyclic ring having from 5 to 7 ring atoms, whereinthe heterocyclic ring optionally contains 1 or 2 additional heteroatomsindependently selected from oxygen, sulfur or nitrogen.

[0133] When part of the group —SO₂NR^(d)R^(e), a specific value forR^(d) and R^(e) independently is alkyl; wherein each alkyl is optionallysubstituted with 1 or 2 alkoxy substituents.

[0134] When part of the group —SO₂NR^(d)R^(e), a specific value forR^(d) or R^(e) is phenyl, or naphthyl; wherein each phenyl and naphthylis optionally substituted with 1, 2, 3, or 4 substituents independentlyselected from halo, C₁₋₆alkyl, C₁₋₆alkoxy, and —CF₃.

[0135] When part of the group —SO₂NR^(d)R^(e), a specific value forR^(d) or R^(e) is heteroaryl; wherein each heteroaryl is optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromhalo, C₁₋₆alkyl, C₁₋₆alkoxy, and —CF₃. Preferably heteroaryl is pyridyl,pyrimidyl, or thiazolyl.

[0136] A preferred group of compounds are compounds wherein R¹¹ or R¹²is —SO₂NR^(d)R^(e); wherein R^(d) is 4-heptyl-6-methyl-2-pyrimidyl,5-methoxy-2-pyrimidyl, 2-pyridyl, phenyl, 2,6-dimethylphenyl,2-thiazoyl, 2-trifluoromethylphenyl, or 3,5-dichlorophenyl; and R^(e) ishydrogen or ethyl.

[0137] Another preferred group of compounds are compounds of theinvention wherein R¹¹ or R¹² is —SO₂NR^(d)R^(e); wherein R^(d) and R^(e)together with the atoms to which they are attached are piperidino ormorpholino.

[0138] A specific group of compounds of the invention are compoundswherein R¹¹ is hydrogen or alkyl; R¹² is —SO₂R^(d); and R¹³ is hydrogen.

[0139] Another specific group of compounds of the invention arecompounds wherein R¹¹ is —SO₂R^(d); R¹² is hydrogen or alkyl; and R¹³ ishydrogen.

[0140] When part of the group —SO₂R^(d), a specific value for R^(d) isalkyl, aryl, or heteroaryl.

[0141] When part of the group —SO₂R^(d), a specific value for R^(d) isaryl optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from halo, C₁₋₆alkyl, C₁₋₆alkoxy, and —CF₃.

[0142] When part of the group —SO₂R^(d), a specific value for R^(d) isphenyl optionally substituted with 1 or 2 substituents independentlyselected from halo and C₁₋₆alkyl.

[0143] A preferred group of compounds of the invention are compoundswherein R¹¹ or R¹² is —SO₂R^(d); wherein R^(d) is phenyl,4-chlorophenyl, methyl, or 4-fluorophenyl.

[0144] A specific group of compounds of the invention are compoundswherein at least one of R¹¹, R¹², and R¹³ is —OR^(d) and each of theother two of R¹¹, R¹², and R¹³ is independently selected from the groupconsisting of hydrogen, alkyl, —O-alkyl, and halo; wherein any alkyl or—O-alkyl is optionally substituted with aryl, or with one or more (e.g.1, 2, 3, or 4) halo substituents.

[0145] A specific group of compounds of the invention are compoundswherein R¹¹ is —OR^(d).

[0146] A specific group of compounds of the invention are compoundswherein R¹² is —OR^(d)

[0147] A specific group of compounds of the invention are compoundswherein R¹³ is —OR^(d)

[0148] A specific group of compounds of the invention are compoundswherein R¹¹ is hydrogen; R¹² is —OR^(d); and R¹³ is hydrogen.

[0149] A specific group of compounds of the invention are compoundswherein R¹¹ is —OR^(d); R¹² is hydrogen; and R¹³ is hydrogen.

[0150] When part of the group —OR^(d), a specific value for R^(d) isalkyl, optionally substituted with one or more (e.g. 1, 2, 3, or 4) halosubstituents and also optionally substituted with 1, 2, 3, or 4 arylsubstituents, wherein each aryl is optionally substituted with 1, 2, 3,or 4 substituents independently selected from halo, C₁₋₆alkyl,C₁₋₆alkoxy, hydroxy, amino, —NHC₁₋₆alkyl, —N(C₁₋₆alkyl)₂,—OC(═O)C₁₋₆alkyl, —C(═O)C₁₋₆alkyl, —C(═O)OC₁₋₆alkyl, —NHC(═O)C₁₋₆alkyl,—C(═O)NHC₁₋₆alkyl, carboxy, nitro, —CN, and —CF₃.

[0151] When part of the group —OR^(d), a specific value for R^(d) isalkyl, optionally substituted with one or more (e.g. 1, 2, 3, or 4) halosubstituents and also optionally substituted with 1 or 2 phenylsubstituents, wherein each phenyl is optionally substituted with 1 or 2substituents independently selected from halo, C₁₋₆alkyl, C₁₋₆alkoxy,hydroxy, —CN, and —CF₃.

[0152] A specific group of compounds of the invention are compoundswherein R¹¹ and R¹² together with the atoms to which they are attachedform a saturated or unsaturated 5, 6, or 7 membered ring comprising oneor more carbon atoms and 1 or 2 heteroatoms independently selected fromoxygen, sulfur or nitrogen; and R¹³ is selected from the groupconsisting of hydrogen, alkyl, —O-alkyl, and halo; wherein any alkyl or—O-alkyl is optionally substituted with aryl, or with one or more (e.g.1, 2, 3, or 4) halo substituents.

[0153] A more specific group of compounds of the invention are compoundswherein R¹¹ and R¹² together are —OCH₂O—, —OCH₂CH₂O—, or —OCH₂CH₂ CH₂O—.

[0154] A specific group of compounds of the invention are compoundswherein R¹¹, R¹² or R¹³ is methoxy, ethoxy, benzyloxy, or isopropoxy.

[0155] A specific group of compounds of the invention are compoundswherein R¹¹, R¹² and R¹³ are each hydrogen.

[0156] A specific group of compounds of the invention are compoundswherein at least one of R¹¹, R¹², and R¹³ is alkyl and each of the othertwo of R¹¹, R¹², and R¹³ is independently selected from the groupconsisting of hydrogen, alkyl, cycloalkyl, hydroxy, and halo, whereinany alkyl is optionally substituted with aryl, with one or more (e.g. 1,2, 3, or 4) halo, or with 1 or 2-O-alkyl substituents; or wherein R¹¹and R¹² together with the atoms to which they are attached form asaturated or unsaturated 5, 6, or 7 membered carbocyclic ring.

[0157] A specific group of compounds of the invention are compoundswherein at least one of R¹¹, R¹², and R¹³ is alkyl and each of the othertwo of R¹¹, R¹², and R¹³ is independently selected from the groupconsisting of hydrogen, alkyl, cycloalkyl, hydroxy, and halo, whereinany alkyl is optionally substituted with aryl, with one or more (e.g. 1,2, 3, or 4) halo, or with 1 or 2-O-alkyl substituents.

[0158] A specific group of compounds of the invention are compoundswherein R¹¹ and R¹² together with the atoms to which they are attachedform a saturated or unsaturated 5, 6, or 7 membered carbocyclic ring;and R¹³ is selected from the group consisting of hydrogen, alkyl,cycloalkyl, hydroxy, and halo, wherein any alkyl is optionallysubstituted with aryl, with one or more (e.g. 1, 2, 3, or 4) halo, orwith 1 or 2-O-alkyl substituents.

[0159] A specific value for R¹³ is hydrogen.

[0160] A specific group of compounds of the invention are compoundswherein R¹¹ is hydrogen; R¹² is alkyl; and R¹³ is hydrogen.

[0161] A specific group of compounds of the invention are compoundswherein R¹¹ is alkyl; R¹² is hydrogen; and R¹³ is hydrogen.

[0162] A preferred group of compounds of the invention are compoundswherein R¹¹ or R¹² is methyl, ethyl, isopropyl, or cyclohexyl; orwherein R¹¹ and R¹² taken together are —CH₂CH₂CH₂—.

[0163] A specific group of compounds of the invention are compoundswherein at least one of R¹¹, R¹², and R¹³ is aryl; and each of the othertwo of R¹¹, R¹², and R¹³ is independently selected from the groupconsisting of hydrogen, alkyl, —O-alkyl, and halo, wherein any alkyl or—O-alkyl is optionally substituted with aryl, with one or more (e.g. l,2, 3, or 4) halo, or with 1 or 2-O-alkyl substituents;

[0164] or wherein R¹¹ and R¹² together with the atoms to which they areattached form a fused benzo ring, which benzo ring can optionally besubstituted with 1, 2, 3, or 4 R^(c); and R¹³ is independently selectedfrom the group consisting of hydrogen, alkyl, —O-alkyl, and halo,wherein any alkyl or —O-alkyl is optionally substituted with aryl, withone or more (e.g. 1, 2, 3, or 4) halo, or with 1 or 2-O-alkylsubstituents.

[0165] A specific group of compounds of the invention are compoundswherein at least one of R¹¹, R¹², and R¹³ is aryl; and each of the othertwo of R¹¹, R¹², and R¹³ is independently selected from the groupconsisting of hydrogen, alkyl, —O-alkyl, and halo, wherein any alkyl or—O-alkyl is optionally substituted with aryl, with one or more (e.g. 1,2, 3, or 4) halo, or with 1 or 2-O-alkyl substituents.

[0166] A specific group of compounds of the invention are compoundswherein R¹¹ is phenyl, optionally substituted with 1, 2, 3, or 4 alkyl,—OR^(d), —NO₂, halo, —NR^(d)R^(e), —C(═O)R^(d), —CO₂R^(d), —OC(═O)R^(d),—CN, —C(═O)NR^(d)R^(e), —NR^(d)C(═O)R^(e), —OC(═O)NR^(d)R^(e),—NR^(d)C(═O)OR^(e), —NR^(d)C(═O)NR^(d)R^(e), —CR^(d)(═N—OR^(e)), —CF₃,or —OCF₃; R¹² is selected from the group consisting of hydrogen and—O-alkyl, optionally substituted with aryl, or with one or more (e.g. 1,2, 3, or 4) halo; and R¹³ is hydrogen.

[0167] A specific group of compounds of the invention are compoundswherein R¹¹ is phenyl, optionally substituted with 1, 2, 3, or 4 alkyl,—OR^(d), halo, —CF₃, or —OCF₃; R¹² is selected from the group consistingof hydrogen and —O-alkyl, optionally substituted with aryl, or with oneor more (e.g. 1, 2, 3, or 4) halo; and R¹³ is hydrogen.

[0168] A specific group of compounds of the invention are compoundswherein R¹¹ or R¹² is phenyl.

[0169] A specific group of compounds of the invention are compoundswherein R¹¹ and R¹² together with the atoms to which they are attachedform a fused benzo ring.

[0170] A specific group of compounds of the invention are compoundswherein at least one of R¹¹, R¹², and R¹³ is heterocyclyl; and each ofthe other two of R¹¹, R¹², and R¹³ is independently selected from thegroup consisting of hydrogen, alkyl, —O-alkyl, and halo, wherein anyalkyl or —O-alkyl is optionally substituted with aryl, with one or more(e.g. 1, 2, 3, or 4) halo, or with 1 or 2-O-alkyl substituents;

[0171] or wherein R¹¹ and R¹² together with the atoms to which they areattached form a heterocyclic ring.

[0172] A specific group of compounds of the invention are compoundswherein R¹¹ and R¹² together with the atoms to which they are attachedform a saturated or unsaturated 5, 6, or 7 membered ring comprisingcarbon atoms and optionally comprising 1 or 2 heteroatoms independentlyselected from oxygen, sulfur or nitrogen, wherein said ring canoptionally be substituted on carbon with one or two oxo (═O), andwherein said ring is fused to a benzo ring, which benzo ring canoptionally be substituted with 1, 2, 3, or 4 R^(e); and R¹³ isindependently selected from the group consisting of hydrogen, alkyl,—O-alkyl, and halo, wherein any alkyl or —O-alkyl is optionallysubstituted with aryl, with one or more halo, or with 1 or 2-O-alkylsubstituents.

[0173] A specific group of compounds of the invention are compoundswherein R¹¹ or R¹² is 2,3-dihydro-5-methyl-3-oxo-1-pyrazolyl; or whereinR¹¹ and R¹² together with the atoms to which they are attached form a2-oxobenzopyran ring.

[0174] Another specific group of compounds of the invention arecompounds wherein R¹¹ or R¹² is anilino, trifluoromethoxy, ormethoxycarbonyl.

[0175] A sub-group of compounds of the invention are compounds offormula (I) wherein each of R¹-R⁵ is independently selected from thegroup consisting of hydrogen, alkyl, and R^(a); wherein each R^(a) isindependently —OR^(d), halo, —NR^(d)R^(e), —NR^(d)C(═O)R^(e), or—OC(═O)NR^(d)R^(e);

[0176] or R¹ and R², or R⁴ and R⁵, are joined together to form a groupselected from the group consisting of —C(R^(d))=C(R^(d))C(═O)NR^(d)—,—CR^(d)R^(d)—CR^(d)R^(d)—C(═O)NR^(d)—, —NR^(d)C(═O)C(R^(d))═C(R^(d))—,—NR^(d)C(═O)CR^(d)R^(d)—CR^(d)R^(d)—, —NR^(d)C(═O)S—, and—SC(═O)NR^(d)—;

[0177] R⁶, R⁸, and R¹⁰ are each hydrogen;

[0178] each of R¹¹ and R¹² is independently selected from the groupconsisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl,heteroaryl, heterocyclyl, —NO₂, halo, —NR^(d)R^(e), —CO₂R^(d),—OC(═O)R^(d), —CN, —C(═O)NR^(d)R^(e), —NR^(d)C(═O)R^(e), —OR^(d),S(O)_(m)R^(d), —NR^(d)—NR^(d)—C(═O)R^(d), —NR^(d)—N═CR^(d)R^(d),—N(NR^(d)R^(e))R^(d), and —S(O)₂NR^(d)R^(e);

[0179] wherein for R¹-R⁵, R¹¹, and R¹², each alkyl is optionallysubstituted with R^(m), or with 1, 2, 3, or 4 substituents independentlyselected from R^(b); for R¹¹ and R¹², each aryl and heteroaryl isoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(c), and for R¹¹ and R¹², each cycloalkyl andheterocyclyl is optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(b) and R^(c);

[0180] R¹³ is hydrogen;

[0181] the group comprising —NR¹⁰ is meta or para to the groupcomprising R⁷; and

[0182] w is 0, 1, or 2.

[0183] Preferably within the above sub-group of compounds, each of R¹¹and R¹² is independently selected from the group consisting of hydrogen,alkyl, cycloalkyl, aryl, heterocyclyl, —OR^(d), —S(O)_(m)R^(d), and—S(O)₂NR^(d)R^(e); wherein each alkyl is optionally substituted with 1or 2 substituents independently selected from R^(b), each aryl isoptionally substituted with 1 or 2 substituents independently selectedfrom R^(c), and each heterocyclyl is optionally substituted with 1 or 2substituents independently selected from R^(b) and R^(c); and m is 0 or2.

[0184] More preferably for such compounds, R⁷ is hydrogen;

[0185] each of R¹¹ and R¹² is independently selected from the groupconsisting of hydrogen, C₁₋₆alkyl, cyclohexyl, phenyl, pyrazolinyl,—OR^(d), —S(O)_(m)R^(d), and —S(O)₂NR^(d)R^(e);

[0186] w is 0; and

[0187] R^(d) and R^(e) are independently selected from the groupconsisting of hydrogen, C₁₋₆alkyl, phenyl, —CF₃, and C₁₋₃alkyl, pyridyl,thiazolyl, pyrimidinyl, and pyrazolinyl, where each phenyl is optionallysubstituted with 1 or 2 substitutents independently selected from halo,—CF₃, and C₁₋₃alkyl, each pyrimidinyl is optionally substituted with 1or 2 substitutents independently selected from C₁₋₃alkyl and OC₁₋₃alkyl,and each pyrazolinyl is optionally substituted with 1 or 2 substitutentsindependently selected from C₁₋₃alkyl and carboxy; or

[0188] R^(d) and R^(e), together with the nitrogen atom to which theyare attached are morpholino or piperidino.

[0189] Within the more preferred sub-group, one most preferred sub-groupof compounds are compounds wherein R¹¹ is —SR^(d) and R¹² is hydrogen,or R¹¹ is hydrogen and R¹² is —SR^(d), wherein R^(d) is selected fromthe group consisting of C₁₋₃alkyl, phenyl, and pyrimidinyl, and whereineach phenyl is optionally substituted with 1 or 2 substitutentsindependently selected from halo and C₁₋₃ alkyl, and each pyrimidinyl isoptionally substituted with C₁₋₃alkyl.

[0190] Another most preferred sub-group of compounds are compoundswherein R¹¹ is —S(O)₂NR^(d)R^(e) and R¹² is hydrogen or alkyl, or R¹¹ ishydrogen or alkyl and R¹² is —S(O)₂NR^(d)R^(e), wherein R^(d) and R^(e)are independently selected from the group consisting of hydrogen,C₁₋₃alkyl, phenyl, pyridyl, thiazolyl, and pyrimidinyl, and wherein eachphenyl is optionally substituted with 1 substitutent selected from haloand C₁₋₃ alkyl, and each pyrimidinyl is optionally substituted with 1substitutent selected from C₁₋₃ alkyl and O—C₁₋₃ alkyl; or R^(d) andR^(e), together with the nitrogen atom to which they are attached aremorpholino or piperidino.

[0191] Another most preferred sub-group of compounds are compoundswherein R¹¹ is —SO₂R^(d) and R¹² is hydrogen, or R¹¹ is hydrogen and R¹²is —SO₂R^(d), wherein Rd is C₁₋₃alkyl or phenyl, and wherein each phenylis optionally substituted with 1 substituent selected from halo andC₁₋₃alkyl.

[0192] Another most preferred sub-group of compounds are compoundswherein R¹¹ is —OR^(d) and R¹² is hydrogen or —OR^(d); or R¹¹ ishydrogen and R¹² is —OR^(d), wherein R^(d) is C₁₋₃alkyl.

[0193] Another most preferred sub-group of compounds are compoundswherein R¹¹ is C₁₋₃alkyl and R¹² is hydrogen or C₁₋₃alkyl; or R¹¹ iscyclohexane and R¹² is hydroxy.

[0194] Another most preferred sub-group of compounds are compoundswherein R¹¹ is hydrogen or phenyl; and R¹² is —OC₁₋₃alkyl; or whereinR¹¹ is phenyl and R¹² is hydrogen.

[0195] Yet another most preferred sub-group of compounds within the morepreferred sub-group defined above are compounds wherein R¹² is hydrogenand R¹¹ is SO₂NR^(d)R^(e), wherein R^(d) and R^(e), together with thenitrogen atom to which they are attached, are morpholino or piperidino.

[0196] Another preferred group of compounds of formula (I) are compoundsof formula (IIa):

[0197] wherein:

[0198] R⁴ is —CH₂OH or —NHCHO and R⁵ is hydrogen; or R⁴ and R⁵ takentogether are —NHC(═O)CH═CH—;

[0199] R¹¹ is phenyl or heteroaryl, wherein each phenyl is optionallysubstituted with 1 or 2 substituents selected from halo, —OR^(d), —CN,—NO₂, —SO₂R^(d), —C(═O)R^(d), —C(═O)NR^(d)R^(e), and C₁₋₃alkyl, whereinC₁₋₃alkyl is optionally substituted with 1 or 2 substituents selectedfrom carboxy, hydroxy, and amino, and each R^(d) and R^(e) isindependently hydrogen or C₁₋₃alkyl; and wherein each heteroaryl isoptionally substituted with 1 or 2 C₁₋₃alkyl substituents; and

[0200] R¹² is hydrogen or —OC₁₋₆alkyl.

[0201] More preferably, for compounds of formula (II), R¹¹ is phenyl,optionally substituted with 1 or 2 substituents selected from halo,—OR^(d), —CN, —NO₂, SO₂R^(d), —C(═O)R^(d), and C₁₋₃alkyl, whereinC₁₋₃alkyl is optionally substituted with 1 or 2 substituents selectedfrom carboxy, hydroxy, and amino, and R^(d) is hydrogen or C₁₋₃alkyl; orR¹¹ is pyridyl, thiophenyl, furanyl, pyrrolyl, isoxazolyl, or indolyl,each of which is optionally substituted with 1 or 2 C₁₋₃alkylsubstituents.

[0202] Most preferable are compounds of formula (IIa), wherein R¹¹ isphenyl, pyridyl, or thiophenyl, wherein each phenyl is optionallysubstituted with 1 substituent selected from the group consisting ofchloro, —OCH₃, —CN, and —CH₂NH₂; and R¹² is hydrogen, —OCH₃, or —OC₂H₅.Among most preferred compounds, particularly preferred are compounds offormula (II) wherein R⁴ and R⁵ taken together are —NHC(═O)CH═CH—, R¹¹ isphenyl or pyridyl, wherein each phenyl is optionally substituted with 1substituent selected from the group consisting of chloro, —OCH₃, —CN,and —CH₂NH₂, and R¹² is —OCH₃.

[0203] Yet another sub-group of compounds of formula (I) are compoundsof formula (IIb):

[0204] wherein:

[0205] R is —CH₂OH or —NHCHO and R⁵ is hydrogen; or R⁴ and R⁵ takentogether are —NHC(═O)CH═CH—;

[0206] R¹² is hydrogen or —OC₁₋₆alkyl;

[0207] R¹⁷ is —(CH₂)_(x)NR^(d)R^(e) wherein each R^(d) and R^(e) isindependently hydrogen or C₁₋₄alkyl, wherein each C₁₋₄alkyl isoptionally substituted with phenyl or pyridyl, or R^(d) and R^(e)together with the nitrogen atom to which they are attached ismorpholino; and

[0208] x is 0, 1, or 2.

[0209] Preferably, for compounds of formula (IIb), R¹² is hydrogen,—OCH₃, or —OC₂H₅; and R¹⁷ is —CH₂NR^(d)R^(e) wherein each R^(d) andR^(e) is independently hydrogen or C₁₋₄alkyl, or R^(d) is hydrogen andRe is C₁₋₄alkyl substituted with phenyl or pyridyl, or R^(d) and R^(e)together with the nitrogen atom to which they are attached ismorpholino. Particularly preferred are compounds of formula (IIb)wherein R⁴ and R⁵ taken together are —NHC(═O)CH═CH— and R¹² and R¹⁷ areas defined immediately above.

[0210] A preferred compound is any one of compounds 1-117 shown in theExamples below.

[0211] Most preferred compounds of the invention include the following:

[0212]N-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine;

[0213]N-{2-[4-(4-ethoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine;

[0214]N-{2-[4-(3-phenylphenyl)aminophenyl]ethyl}-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine;

[0215]N-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;

[0216]N-{2-[4-(4-methoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine;

[0217]N-{2-[4-(3-phenyl-4-ethoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine;

[0218]N-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine;

[0219]N-{2-[4-(4-ethoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine;

[0220]N-{2-[4-(3-phenylphenyl)aminophenyl]ethyl}-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine;

[0221]N-{2-[4-(3-phenyl-4-ethoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine;

[0222]N-{2-[4-(4-methoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine;

[0223]N-{2-[4-(4-ethoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;

[0224]N-{2-[4-(3-phenylphenyl)aminophenyl]ethyl}-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;

[0225]N-{2-[4-(3-phenyl-4-ethoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;and

[0226]N-{2-[4-(4-methoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;

[0227]N-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine;

[0228]N-{2-[4-(4-ethoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine;

[0229]N-{2-[4-(3-phenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine;

[0230]N-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;

[0231]N-{2-[4-(4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine;

[0232]N-{2-[4-(3-phenyl-4-ethoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine;

[0233]N-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine;

[0234]N-{2-[4-(4-ethoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine;

[0235]N-{2-[4-(3-phenylphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine;

[0236]N-{2-[4-(3-phenyl-4-ethoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine;

[0237]N-{2-[4-(4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine;

[0238]N-{2-[4-(4-ethoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;

[0239]N-{2-[4-(3-phenylphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;N-{2-[4-(3-phenyl-4-ethoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;

[0240]N-{2-[4-(4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;

[0241]N-{2-[4-(3-(2-chlorophenyl)phenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;

[0242]N-{2-[4-(3-(2-methoxyphenyl)phenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;

[0243]N-{2-[4-(3-(3-cyanophenyl)phenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;

[0244]N-{2-[4-(3-(4-aminomethylphenyl)phenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;

[0245]N-{2-[4-(3-(3-chlorophenyl)phenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;

[0246]N-{2-[4-(3-(4-aminomethylphenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;

[0247]N-{2-[4-(3-(3-cyanophenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;

[0248]N-{2-[4-(3-(4-hydroxyphenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;

[0249]N-{2-[4-(3-(3-pyridyl)phenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;

[0250]N-{2-[4-(3-(3-pyridyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;

[0251]N-{2-[4-(3-(4-pyridyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;

[0252]N-{2-[4-(3-(thiophen-3-yl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1h)-quinolinon-5-yl)ethylamine;

[0253]N-{2-[4-(3-(3-chlorophenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;and

[0254]N-{2-[4-(3-(3-aminomethylphenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine.

[0255] Particular mention may be made of the following compounds, forwhich the compound numbers used in the following examples are indicatedin parentheses:

[0256]N-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine(61);

[0257]N-{2-[4-(3-(4-aminomethylphenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine(96);

[0258]N-{2-[4-(3-(3-cyanophenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine(95);

[0259]N-{2-[4-(3-(3-chlorophenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine(102); and

[0260]N-{2-[4-(3-(3-aminomethylphenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine(112).

[0261] A consistent chemical nomenclature is employed throughout thisapplication. In an alternative nomenclature, using the automatic namingprogram AutoNom, as provided by MDL Information Systems, GmbH(Frankfurt, Germany), compound 61, for example, is referenced as8-hydroxy-5-((R)-1-hydroxy-2-{2-[4-(6-methoxy-biphenyl-3-ylamino)-phenyl]-ethylamino}1-ethyl)-1H-quinolin-2-one.

[0262] As described throughout, the invention also includespharmaceutically-acceptable salts of the compounds of the invention. Apreferred pharmaceutically-acceptable salt of compound 61 is thehydrochloride salt.

[0263] The compounds of the invention contain one or more chiral centersAccordingly, the invention includes racemic mixtures, pure stereoisomers(i.e. individual enantiomers or diastereomers), andstereoisomer-enriched mixtures of such isomers, unless otherwiseindicated. When a particular stereoisomer is shown, it will beunderstood by those skilled in the art, that minor amounts of otherstereoisomers may be present in the compositions of this inventionunless otherwise indicated, provided that the utility of the compositionas a whole is not eliminated by the presence of such other isomers. Inparticular, compounds of the invention contain a chiral center at thealkylene carbon in formulas (I) and (II) to which the hydroxy group isattached. When a mixture of stereoisomers is employed, it isadvantageous for the amount of the stereoisomer with the (R) orientationat the chiral center bearing the hydroxy group to be greater than theamount of the corresponding (S) stereoisomer. When comparingstereoisomers of the same compound, the (R) stereoisomer is preferredover the (S) stereoisomer.

[0264] General Synthetic Procedures

[0265] The compounds of the invention can be prepared using the methodsand procedures described herein, or using similar methods andprocedures. It will be appreciated that where typical or preferredprocess conditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. Optimum reactionconditions may vary with the particular reactants or solvent used, butsuch conditions can be determined by one skilled in the art by routineoptimization procedures.

[0266] Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be used to prevent certain functionalgroups from undergoing undesired reactions. The choice of a suitableprotecting group for a particular functional group, as well as suitableconditions for protection and deprotection, are well known in the art.Representative examples of amino-protecting groups andhydroxy-protecting groups are given above. Typical procedures for theirremoval include the following. An acyl amino-protecting group orhydroxy-protecting group may conveniently be removed, for example, bytreatment with an acid, such as trifluoroacetic acid. An arylmethylgroup may conveniently be removed by hydrogenolysis over a suitablemetal catalyst such as palladium on carbon. A silyl hydroxy-protectinggroup may conveniently be removed by treatment with a fluoride ionsource, such as tetrabutylammonium fluoride, or by treatment with anacid, such as hydrochloric acid.

[0267] In addition, numerous protecting groups (includingamino-protecting groups and hydroxy-protecting groups), and theirintroduction and removal, are described in Greene and Wuts, ProtectingGroups in Organic Synthesis, 2nd Edition, John Wiley & Sons, NY, 1991,and in McOmie, Protecting Groups in Organic Chemistry, Plenum Press, NY,1973.

[0268] Processes for preparing compounds of the invention are providedas further embodiments of the invention and are illustrated by theprocedures below.

[0269] A compound of formula (I) can be prepared by deprotecting acorresponding compound of formula (III):

[0270] wherein R¹⁵ is an amino-protecting group. Accordingly, theinvention provides a method for preparing a compound of formula (I),comprising deprotecting a corresponding compound of formula (III),wherein R¹⁵ is an amino-protecting group (e.g.1,1-(4-methoxyphenyl)methyl or benzyl).

[0271] A compound of formula (I) wherein R³ is hydroxy can be preparedby deprotecting a corresponding compound of formula (I) wherein R³ is—OPg¹ and Pg¹ is a hydroxy-protecting group. Accordingly, the inventionprovides a method for preparing a compound of formula (I) wherein R³ ishydroxy, comprising deprotecting a corresponding compound of formula (I)wherein R³ is —OPg¹ and Pg¹ is a hydroxy-protecting group (e.g. benzyl).

[0272] A compound of formula (I) wherein R³ is hydroxy can also beprepared by deprotecting a corresponding compound of formula (III)wherein R 5 is an amino-protecting group and wherein R³ is —OPg¹ whereinPg¹ is a hydroxy-protecting group. Accordingly, the invention provides amethod for preparing a compound of formula (I), comprising deprotectinga corresponding compound of formula (E) wherein R¹⁵ is anamino-protecting group (e.g. benzyl) and R³ is —OPg¹ wherein Pg¹ is ahydroxy-protecting group (e.g. benzyl).

[0273] The invention also provides an intermediate compound of formula(III) wherein R¹⁵ is an amino-protecting group (e.g.1,1-di-(4′-methoxyphenyl)methyl or benzyl); as well as an intermediatecompound of formula (I) wherein R³ is —OPg¹ and Pg¹ is ahydroxy-protecting group; and an intermediate compound of formula (III)wherein R¹⁵ is an amino-protecting group (e.g. benzyl), R³ is —OPg¹, andPg₁ is a hydroxy-protecting group (e.g. benzyl).

[0274] An intermediate compound of formula (III) can be prepared byreacting an amine of formula (V) with a compound of formula (IV),wherein R¹⁶ is hydrogen or a hydroxy-protecting group (e.g.tert-butyldimethylsilyl) and X is a suitable leaving group (e.g. bromo).

[0275] Accordingly, the invention provides a method for preparing acompound of formula (III), comprising reacting a corresponding anilineof formula (V) with a corresponding compound of formula (IV), wherein Xis a suitable leaving group (e.g. bromo) and R¹⁵ is an amino-protectinggroup, in the presence of a transition metal catalyst. When R is ahydroxy-protecting group, the intermediate formed by the reaction of acompound of formula (V) with a compound of formula (IV) is subsequentlydeprotected to form the intermediate of formula (III). Suitableconditions for this reaction as well as suitable leaving groups areillustrated in the Examples and are also known in the art.

[0276] A compound of formula (III) can also be prepared by reacting anamine of formula (VII):

[0277] wherein R¹⁴ is hydrogen and R¹⁵ is an amino-protecting group(e.g. benzyl), with a compound of formula (VI), (VIII), or (IX):

[0278] wherein R¹⁶ is hydrogen or a hydroxy-protecting group (e.g.tert-butyldimethylsilyl) and Z is a leaving group.

[0279] Accordingly, the invention provides a method for preparing acompound of formula (III), comprising reacting a corresponding amine offormula (VII), wherein R¹⁴ is hydrogen and R¹⁵ is an amino-protectinggroup, with a corresponding compound of formula (VI), (VIII), or (IX),wherein R¹⁶ is hydrogen or a hydroxy-protecting group and Z is asuitable leaving group (e.g. bromo). When R is a hydroxy-protectinggroup, the intermediate formed by the reaction of a compound of formula(VII) with a compound of formula (VI) is subsequently deprotected toform the intermediate of formula (III).

[0280] The invention also provides a method for preparing a compound offormula (I), wherein R³ is —OPg¹ and Pg¹ is a hydroxy-protecting group,comprising reacting a corresponding compound of formula (VII) whereinR¹⁴ and R¹⁵ are each hydrogen with a corresponding compound of formula(VI), wherein R³ is —OPg¹ and Pg¹ is a hydroxy-protecting group and R¹⁶is a hydroxy-protecting group.

[0281] Depending on the specific values of the substituents, variationson the synthetic schemes described above can be employed, particularlyin the order of coupling and deprotection reactions, to produce acompound of the invention. For example, a compound of formula (I)wherein R³ is hydroxy and R¹³ is hydrogen can be prepared by reacting anintermediate of formula (I) wherein R³ is —OPg¹, where Pg¹ is ahydroxy-protecting group, and R¹¹ is a suitable leaving group (e.g.bromo) with an appropriately substituted boronic acid to form anintermediate, which is subsequently deprotected, as illustrated inExamples 65-102.

[0282] According to yet another method, a compound of formula (I) can beprepared by coupling an intermediate of formula (IV) wherein R¹⁵ ishydrogen and R¹⁶ is a hydroxy-protecting group with a compound offormula (V), where the remaining variables are defined as in formula(I), in the presence of a transition metal catalyst, typicallypalladium, to form a protected intermediate, followed by removing theprotecting group R¹⁶ to form a compound of formula (I).

[0283] To form a compound of formula (I) wherein R³ is hydroxy, acompound of formula (IV) wherein R³ is —OPg¹ and Pg¹ is ahydroxy-protecting group, for example benzyl, is used in the abovemethod to provide an intermediate of formula (I) in which R³ is —OPg¹,from which the protecting group Pg¹ is removed to form the product offormula (I) having a hydroxy at R³.

[0284] A palladium-based catalyst is typically used in the process ofcoupling intermediates (IV) and (V) to provide a diarylamine compound offormula (I). As a result the compounds of this invention orintermediates thereof can be contaminated with unacceptable levels ofpalladium impurities. It has now been discovered that such palladiumimpurities can be removed from compounds of this invention orintermediates thereof using a functionalized solid support comprising(1-thioureido)alkyl or (mercapto)alkyl groups.

[0285] The compound to be purified of palladium is dissolved in asolvent compatible with the solid support, where a compatible solvent isone that does not affect the performance of the functionalized solidsupport. If the compound is in a free base form, an amount of acid,preferably hydrochloric acid, sufficient to convert the basic nitrogensof the compound to protonated form is added. Between about 1.05 andabout 1.2 equivalents of HCl per basic nitrogen is a sufficient amount.The resulting solution is diluted further with solvent and afunctionalized solid support comprising (1-thioureido)alkyl or(mercapto)alkyl groups is added. Preferably the solid support is asilica gel comprising 3-(1-thioureido)propyl or 3-(mercapto)propylgroups. Preferably between about 5 and about 15 weight % of thefunctionalized silica gel is added. A preferred solvent compatible withthe functionalized silica gel is a mixture of dichloromethane andmethanol.

[0286] The resulting solution is separated from the solid support andthe product is isolated. For example, the solution is stirred at roomtemperature for several hours followed by filtration through filterpaper. The remaining silica is washed with additional solvent. Combinedfiltrates are washed with saturated aqueous sodium bicarbonate andbrine. The organic solution is treated with anhydrous sodium sulfate,filtered and evaporated under reduced pressure to give the product. Thepurification of an intermediate in the preparation of compound 61 bythis process is described in detail in Example 61C part f.

[0287] Accordingly, in yet another method aspect, this inventionprovides a method of reducing the amount of palladium in a compositioncomprising a diarylamine compound and palladium, the method comprising(a) contacting a solution comprising a diarylamine compound having oneor more basic nitrogen atoms wherein each nitrogen atom has beenprotonated with an acid, palladium, and a solvent, with a functionalizedsolid support comprising (1-thioureido)alkyl or (mercapto)alkyl groups;and (b) separating the resulting solution from the solid support toprovide a composition having a reduced amount of palladium, wherein thesolvent is compatible with the functionalized solid support. Inaddition, the invention provides a method of reducing palladium in acomposition wherein the diarylamine compound isN-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-benzyloxy-2(1H)-quinolinon-5-yl)ethylamine.Preferably, in the method of removing palladium from the diarylaminecompound immediately above, the acid is hydrochloric acid; the solventcomprises a mixture of dichloromethane and methanol, and thefunctionalized solid support is a silica gel comprising3-(1-thioureido)propyl or 3-(mercapto)propyl groups.

[0288] The invention further provides a compound produced by the processcomprising (a) coupling an intermediate of formula (IV) wherein R¹⁵ ishydrogen and R¹⁶ is a hydroxy-protecting group with a compound offormula (V), where the remaining variables are defined as in formula (I)and R³ can additionally be defined as —OPg¹, in the presence of apalladium catalyst, to form a protected intermediate; (b) removing theprotecting group R¹⁶ from the protected intermediate to form a compoundof formula (I); (c) contacting a solution comprising the compound offormula (I), wherein each nitrogen atom has been protonated with anacid, and a solvent, with a functionalized solid support comprising(1-thioureido)alkyl or 3-(mercapto)alkyl groups, wherein the solvent iscompatible with the functionalized solid support; (d) separating theresulting solution from the functionalized solid support; and, when R³is —OPg¹, (d) removing the protecting group to form a compound in whichR³ is hydroxy.

[0289] In addition, the invention provides a compound produced by theprocess immediately above wherein R¹, R², R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹³are each hydrogen, R³ is —OPg¹ wherein Pg¹ is benzyl, R⁴ and R⁵takentogether are —NHC(═O)CH═CH—, R¹¹ is phenyl, R¹² is —OCH₃, the leavinggroup X in formula (IV) is attached at the para position; the acid ishydrochloric acid; the solvent is a mixture of dichloromethane andmethanol, and the functionalized solid support is a silica gelcomprising 3-(1-thioureido)propyl or 3-(mercapto)propyl groups.

[0290] Additionally, a useful intermediate for preparing a compound offormula (VII), wherein R¹⁴ is hydrogen and R¹⁵ is an amino-protectinggroup, is a corresponding compound of formula (VII) wherein R¹⁴ is anamino-protecting group that can be removed in the presence of R¹⁵. Acompound of formula (VII) wherein R¹⁴ is hydrogen and R¹⁵ is anamino-protecting group is itself also a useful intermediate for thepreparation of a compound of formula (VII) where both R¹⁴ and R¹⁵ arehydrogen. Thus, the invention also provides novel intermediates offormula (VII), wherein R¹⁴ is hydrogen or an amino-protecting group, R¹⁵is hydrogen or an amino-protecting group, and wherein R⁷-R¹³ and w haveany of the values defined herein, or a salt thereof.

[0291] A preferred compound of formula (VII) is a compound wherein R¹⁴and R¹⁵ are both hydrogen. Another preferred compound of formula (VII)is a compound wherein R¹⁴ is an alkoxycarbonyl protecting group (e.g.tert-butoxy carbonyl), and R¹⁵ is an arylmethyl protecting group (e.g.benzyl). Another preferred compound of formula (VII) is a compoundwherein R¹⁴ is hydrogen, and R¹⁵ is an alkoxycarbonyl protecting group(e.g. tert-butoxy carbonyl).

[0292] Pharmaceutical Compositions

[0293] The invention also provides pharmaceutical compositionscomprising a compound of the invention. Accordingly, the compound,preferably in the form of a pharmaceutically-acceptable salt, can beformulated for any suitable form of administration, such as oral orparenteral administration, or administration by inhalation.

[0294] By way of illustration, the compound can be admixed withconventional pharmaceutical carriers and excipients and used in the formof powders, tablets, capsules, elixirs, suspensions, syrups, wafers, andthe like. Such pharmaceutical compositions will contain from about 0.05to about 90% by weight of the active compound, and more generally fromabout 0.1 to about 30%. The pharmaceutical compositions may containcommon carriers and excipients, such as cornstarch or gelatin, lactose,magnesium sulfate, magnesium stearate, sucrose, microcrystallinecellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride, andalginic acid. Disintegrators commonly used in the formulations of thisinvention include croscarmellose, microcrystalline cellulose,cornstarch, sodium starch glycolate and alginic acid.

[0295] A liquid composition will generally consist of a suspension orsolution of the compound or pharmaceutically-acceptable salt in asuitable liquid carrier(s), for example ethanol, glycerine, sorbitol,non-aqueous solvent such as polyethylene glycol, oils or water,optionally with a suspending agent, a solubilizing agent (such as acyclodextrin), preservative, surfactant, wetting agent, flavoring orcoloring agent. Alternatively, a liquid formulation can be prepared froma reconstitutable powder.

[0296] For example a powder containing active compound, suspendingagent, sucrose and a sweetener can be reconstituted with water to form asuspension; a syrup can be prepared from a powder containing activeingredient, sucrose and a sweetener.

[0297] A composition in the form of a tablet can be prepared using anysuitable pharmaceutical carrier(s) routinely used for preparing solidcompositions. Examples of such carriers include magnesium stearate,starch, lactose, sucrose, microcrystalline cellulose and binders, forexample polyvinylpyrrolidone. The tablet can also be provided with acolor film coating, or color included as part of the carrier(s). Inaddition, active compound can be formulated in a controlled releasedosage form as a tablet comprising a hydrophilic or hydrophobic matrix.

[0298] A composition in the form of a capsule can be prepared usingroutine encapsulation procedures, for example by incorporation of activecompound and excipients into a hard gelatin capsule. Alternatively, asemi-solid matrix of active compound and high molecular weightpolyethylene glycol can be prepared and filled into a hard gelatincapsule; or a solution of active compound in polyethylene glycol or asuspension in edible oil, for example liquid paraffin or fractionatedcoconut oil can be prepared and filled into a soft gelatin capsule.

[0299] Tablet binders that can be included are acacia, methylcellulose,sodium carboxymethylcellulose, poly-vinylpyrrolidone (Povidone),hydroxypropyl methylcellulose, sucrose, starch and ethylcellulose.Lubricants that can be used include magnesium stearate or other metallicstearates, stearic acid, silicone fluid, talc, waxes, oils and colloidalsilica.

[0300] Flavoring agents such as peppermint, oil of wintergreen, cherryflavoring or the like can also be used. Additionally, it may bedesirable to add a coloring agent to make the dosage form moreattractive in appearance or to help identify the product.

[0301] The compounds of the invention and theirpharmaceutically-acceptable salts that are active when givenparenterally can be formulated for intramuscular, intrathecal, orintravenous administration.

[0302] A typical composition for intra-muscular or intrathecaladministration will consist of a suspension or solution of activeingredient in an oil, for example arachis oil or sesame oil. A typicalcomposition for intravenous or intrathecal administration will consistof a sterile isotonic aqueous solution containing, for example activeingredient and dextrose or sodium chloride, or a mixture of dextrose andsodium chloride. Other examples are lactated Ringer's injection,lactated Ringer's plus dextrose injection, Normosol-M and dextrose,Isolyte E, acylated Ringer's injection, and the like. Optionally, aco-solvent, for example, polyethylene glycol; a chelating agent, forexample, ethylenediamine tetracetic acid; a solubilizing agent, forexample, a cyclodextrin; and an anti-oxidant, for example, sodiummetabisulphite, may be included in the formulation. Alternatively, thesolution can be freeze dried and then reconstituted with a suitablesolvent just prior to administration.

[0303] The compounds of this invention and theirpharmaceutically-acceptable salts which are active on topicaladministration can be formulated as transdermal compositions ortransdermal delivery devices (“patches”). Such compositions include, forexample, a backing, active compound reservoir, a control membrane, linerand contact adhesive. Such transdermal patches may be used to providecontinuous or discontinuous infusion of the compounds of the presentinvention in controlled amounts. The construction and use of transdermalpatches for the delivery of pharmaceutical agents is well known in theart. See, for example, U.S. Pat. No. 5,023,252. Such patches may beconstructed for continuous, pulsatile, or on demand delivery ofpharmaceutical agents.

[0304] One preferred manner for administering a compound of theinvention is inhalation. Inhalation is an effective means for deliveringan agent directly to the respiratory tract. There are three generaltypes of pharmaceutical inhalation devices: nebulizer inhalers, drypowder inhalers (DPI), and metered-dose inhalers (MDI). Nebulizerdevices produce a stream of high velocity air that causes a therapeuticagent to spray as a mist which is carried into the patient's respiratorytract. The therapeutic agent is formulated in a liquid form such as asolution or a suspension of micronized particles of respirable size,where micronized is typically defined as having about 90% or more of theparticles with a diameter of less than about 10 μm. A typicalformulation for use in a conventional nebulizer device is an isotonicaqueous solution of a pharmaceutical salt of the active agent at aconcentration of the active agent of between about 0.05 μg/mL and about10 mg/mL.

[0305] DPI's typically administer a therapeutic agent in the form of afree flowing powder that can be dispersed in a patient's air-streamduring inspiration. In order to achieve a free flowing powder, thetherapeutic agent can be formulated with a suitable excipient, such aslactose or starch. A dry powder formulation can be made, for example, bycombining dry lactose having a particle size between about 1 μm andabout 100 μm with micronized particles of a pharmaceutical salt of theactive agent and dry blending. Alternative, the agent can be formulatedwithout excipients. The formulation is loaded into a dry powderdispenser, or into inhalation cartridges or capsules for use with a drypowder delivery device.

[0306] Examples of DPI delivery devices provided commercially includeDiskhaler (GlaxoSmithKline, Research Triangle Park, N.C.) (see, e.g.,U.S. Pat. No. 5,035,237); Diskus (GlaxoSmithKline) (see, e.g., U.S. Pat.No. 6,378,519; Turbuhaler (AstraZeneca, Wilmington, Del.) (see, e.g.,U.S. Pat. No. 4,524,769); and Rotahaler (GlaxoSmithKline) (see, e.g.,U.S. Pat. No. 4,353,365). Further examples of suitable DPI devices aredescribed in U.S. Pat. Nos. 5,415,162, 5,239,993, and 5,715,810 andreferences therein.

[0307] MDI's typically discharge a measured amount of therapeutic agentusing compressed propellant gas. Formulations for MDI administrationinclude a solution or suspension of active ingredient in a liquefiedpropellant. While chlorofluorocarbons, such as CCl₃F, conventionallyhave been used as propellants, due to concerns regarding adverse affectsof such agents on the ozone layer, formulations usinghydrofluoroalklanes (HFA), such as 1,1,1,2-tetrafluoroethane (HFA 134a)and 1,1,1,2,3,3,3,-heptafluoro-n-propane, (HFA 227) have been developed.Additional components of HFA formulations for MDI administration includeco-solvents, such as ethanol or pentane, and surfactants, such assorbitan trioleate, oleic acid, lecithin, and glycerin. (See, forexample, U.S. Pat. No. 5,225,183, EP 0717987 A2, and WO 92/22286.)

[0308] Thus, a suitable formulation for MDI administration can includefrom about 0.01% to about 5% by weight of a pharmaceutical salt ofactive ingredient, from about 0% to about 20% by weight ethanol, andfrom about 0% to about 5% by weight surfactant, with the remainder beingthe HFA propellant. In one approach, to prepare the formulation, chilledor pressurized hydrofluoroalkane is added to a vial containing thepharmaceutical salt of active compound, ethanol (if present) and thesurfactant (if present). To prepare a suspension, the pharmaceuticalsalt is provided as micronized particles. The formulation is loaded intoan aerosol canister, which forms a portion of an MDI device. Examples ofMDI devices developed specifically for use with HFA propellants areprovided in U.S. Pat. Nos. 6,006,745 and 6,143,277.

[0309] In an alternative preparation, a suspension formulation isprepared by spray drying a coating of surfactant on micronized particlesof a pharmaceutical salt of active compound. (See, for example, WO99/53901 and WO 00/61108.) For additional examples of processes ofpreparing respirable particles, and formulations and devices suitablefor inhalation dosing see U.S. Pat. Nos. 6,268,533, 5,983,956,5,874,063, and 6,221,398, and WO 99/55319 and WO 00/30614.

[0310] It will be understood that any form of the compounds of theinvention, (i.e. free base, pharmaceutical salt, or solvate) that issuitable for the particular mode of administration, can be used in thepharmaceutical compositions discussed above.

[0311] The active compounds are effective over a wide dosage range andare generally administered in a therapeutically effective amount. Itwill be understood, however, that the amount of the compound actuallyadministered will be determined by a physician, in the light of therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered and itsrelative activity, the age, weight, and response of the individualpatient, the severity of the patient's symptoms, and the like.

[0312] Suitable doses of the therapeutic agents for inhalationadministration are in the general range of from about 0.05 μg/day toabout 1000 μg/day, preferably from about 0.5 μg/day to about 500 μg/day.A compound can be administered in a periodic dose: weekly, multipletimes per week, daily, or multiple doses per day. The treatment regimenmay require administration over extended periods of time, for example,for several weeks or months, or the treatment regimen may requirechronic administration. Suitable doses for oral administration are inthe general range of from about 0.05 μg/day to about 100 mg/day,preferably 0.5 to 1000 μg/day.

[0313] The present active agents can also be co-administered with one ormore other therapeutic agents. For example, the present agents can beadministered in combination with one or more therapeutic agents selectedfrom anti-inflammatory agents (e.g. corticosteroids and non-steroidalanti-inflammatory agents (NSAIDs), antichlolinergic agents (particularlymuscarinic receptor antagonists), other β₂ adrenergic receptor agonists,antiinfective agents (e.g. antibiotics or antivirals) or antihistamines.The invention thus provides, in a further aspect, a combinationcomprising a compound of the invention together with one or moretherapeutic agent, for example, an anti-inflammatory agent, anantichlolinergic agent, another β₂ adrenergic receptor agonist, anantiinfective agent or an antihistamine.

[0314] The other therapeutic agents can be used in the form ofpharmaceutically acceptable salts or solvates. As appropriate, the othertherapeutic agents can be used as optically pure stereoisomers.

[0315] Suitable anti-inflammatory agents include corticosteroids andNSAIDs. Suitable corticosteroids which may be used in combination withthe compounds of the invention are those oral and inhaledcorticosteroids and their pro-drugs which have anti-inflammatoryactivity. Examples include methyl prednisolone, prednisolone,dexamethasone, fluticasone propionate,6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester,6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3S-yl) ester, beclomethasone esters (e.g.the 17-propionate ester or the 17,21-dipropionate ester), budesonide,flunisolide, mometasone esters (e.g. the furoate ester), triamcinoloneacetonide, rofleponide, ciclesonide, butixocort propionate, RPR-106541,and ST-126. Preferred corticosteroids include fluticasone propionate,6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-[(4-methyl-1,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester and6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester, more preferably6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester.

[0316] Suitable NSAIDs include sodium cromoglycate; nedocromil sodium;phosphodiesterase (PDE) inhibitors (e.g. theophylline, PDE4 inhibitorsor mixed PDE3/PDE4 inhibitors); leukotriene antagonists (e.g.monteleukast); inhibitors of leukotriene synthesis; iNOS inhibitors;protease inhibitors, such as tryptase and elastase inhibitors; beta-2integrin antagonists and adenosine receptor agonists or antagonists(e.g. adenosine 2a agonists); cytokine antagonists (e.g. chemokineantagonists such as, an interleukin antibody (αIL antibody),specifically, an αIL-4 therapy, an αIL-13 therapy, or a combinationthereof); or inhibitors of cytokine synthesis. Suitable otherβ₂-adrenoreceptor agonists include salmeterol (e.g. as the xinafoate),salbutamol (e.g. as the sulphate or the free base), formoterol (e.g. asthe fumarate), fenoterol or terbutaline and salts thereof.

[0317] Also of interest is use of the present active agent incombination with a phosphodiesterase 4 (PDE4) inhibitor or a mixedPDE3/PDE4 inhibitor. The PDE4-specific inhibitor useful in this aspectof the invention may be any compound that is known to inhibit the PDE4enzyme or which is discovered to act as a PDE4 inhibitor, and which areonly PDE4 inhibitors, not compounds which inhibit other members of thePDE family as well as PDE4. Generally it is preferred to use a PDE4inhibitor which has an IC₅₀ ratio of about 0.1 or greater as regards theIC₅₀ for the PDE4 catalytic form which binds rolipram with a highaffinity divided by the IC₅₀ for the form which binds rolipram with alow affinity. For the purposes of this disclosure, the cAMP catalyticsite which binds R and S rolipram with a low affinity is denominated the“low affinity” binding site (LPDE 4) and the other form of thiscatalytic site which binds rolipram with a high affinity is denominatedthe “high affinity” binding site (HPDE 4). This term “HPDE4” should notbe confused with the term “hPDE4” which is used to denote human PDE4.

[0318] A method for determining IC₅₀ ratios is set out in U.S. Pat. No.5,998,428 which is incorporated herein by reference. See also PCTapplication WO 00/51599 for another description of the assay.

[0319] The preferred PDE4 inhibitors of use in this invention will bethose compounds which have a salutary therapeutic ratio, i.e., compoundswhich preferentially inhibit cAMP catalytic activity where the enzyme isin the form that binds rolipram with a low affinity, thereby reducingthe side effects which apparently are linked to inhibiting the formwhich binds rolipram with a high affinity. Another way to state this isthat the preferred compounds will have an IC₅₀ ratio of about 0.1 orgreater as regards the IC₅₀ for the PDE4 catalytic form which bindsrolipram with a high affinity divided by the IC₅₀ for the form whichbinds rolipram with a low affinity.

[0320] A further refinement of this standard is one wherein the PDE4inhibitor has an IC₅₀ ratio of about 0.1 or greater; wherein said ratiois the ratio of the IC₅₀ value for competing with the binding of 1 nM of[³H]R-rolipram to a form of PDE4 which binds rolipram with a highaffinity to the IC₅₀ value for inhibiting the PDE4 catalytic activity ofa form which binds rolipram with a low affinity using 1 μM[³H]-cAMP asthe substrate.

[0321] Most preferred are those PDE4 inhibitors which have an IC₅₀ ratioof greater than 0.5, and particularly those compounds having a ratio ofgreater than 1.0. Preferred compounds are cis4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylicacid,2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-oneandcis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol];these are examples of compounds which bind preferentially to the lowaffinity binding site and which have an IC₅₀ ratio of 0.1 or greater.

[0322] Other compounds of interest include:

[0323] Compounds set out in U.S. Pat. No. 5,552,438 issued 03 September,1996; this patent and the compounds it discloses are incorporated hereinin full by reference. The compound of particular interest, which isdisclosed in U.S. Pat. No. 5,552,438, iscis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxylicacid (also known as cilomalast) and its salts, esters, pro-drugs orphysical forms;

[0324] AWD-12-281 from elbion (Hofgen, N. et al. 15th EFMC Int Symp MedChem (Sept 6-10, Edinburgh) 1998, Abst P.98; CAS reference No.247584020-9); a 9-benzyladenine derivative nominated NCS-613 (INSERM);D-4418 from Chiroscience and Schering-Plough; a benzodiazepine PDE4inhibitor identified as CI-1018 (PD-168787) and attributed to Pfizer; abenzodioxole derivative disclosed by Kyowa Hakko in WO99/16766; K-34from Kyowa Hakko; V-I 1294A from Napp (Landells, L. J. et al. Eur Resp J[Annu Cong Eur Resp Soc (Sept 19-23, Geneva) 1998] 1998, 12 (Suppl. 28):Abst β₂₃₉₃); roflumilast (CAS reference No 162401-32-3) and apthalazinone (WO99/47505, the disclosure of which is hereby incorporatedby reference) from Byk-Gulden; Pumafentrine, (−)-p-[(4aR*,10bS*)-9-ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbenzo[c][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamidewhich is a mixed PDE3/PDE4 inhibitor which has been prepared andpublished on by Byk-Gulden, now Altana; arofylline under development byAlmirall-Prodesfarma; VM554/UM565 from Vernalis; or T-440 (TanabeSeiyaku; Fuji, K. et al. J Pharmacol Exp Ther,1998, 284(1): 162), andT2585.

[0325] Other possible PDE-4 and mixed PDE3/PDE4 inhibitors include thoselisted in WO01/13953, the disclosure of which is hereby incorporated byreference.

[0326] Suitable anticholinergic agents are those compounds that act asantagonists at the muscarinic receptor, in particular those compoundswhich are antagonists of the M₁, M₂, or M₃ receptors, or of combinationsthereof. Exemplary compounds include the alkaloids of the belladonnaplants as illustrated by the likes of atropine, scopolamine,homatropine, hyoscyamine; these compounds are normally administered as asalt, being tertiary amines. These drugs, particularly the salt forms,are readily available from a number of commercial sources or can be madeor prepared from literature data via, to wit:

[0327] Atropine-CAS-51-55-8 or CAS-51-48-1 (anhydrous form), atropinesulfate-CAS-5908-99-6; atropine oxide-CAS-4438-22-6 or its HClsalt-CAS-4574-60-1 and methylatropine nitrate-CAS-52-88-0.

[0328] Homatropine-CAS-87-00-3, hydrobromide salt-CAS-51-56-9,methylbromide salt-CAS-80-49-9.

[0329] Hyoscyamine (d, 1)-CAS-101-31-5, hydrobromide salt-CAS-306-03-6and sulfate salt-CAS-6835-16-1.

[0330] Scopolamine-CAS-51-34-3, hydrobromide salt-CAS-6533-68-2,methylbromide salt-CAS-155-41-9.

[0331] Preferred anticholinergics include ipratropium (e.g. as thebromide), sold under the name Atrovent, oxitropium (e.g. as the bromide)and tiotropium (e.g. as the bromide) (CAS-139404-48-1). Also of interestare: methantheline (CAS-53-46-3), propantheline bromide (CAS-50-34-9),anisotropine methyl bromide or Valpin 50 (CAS-80-50-2), clidiniumbromide (Quarzan, CAS-3485-62-9), copyrrolate (Robinul), isopropamideiodide (CAS-71-81-8), mepenzolate bromide (U.S. Pat. No. 2,918,408),tridihexethyl chloride (Pathilone, CAS-4310-35-4), and hexocycliummethylsulfate (Tral, CAS-115-63-9). See also cyclopentolatehydrochloride (CAS-5870-29-1), tropicamide (CAS-1508-75-4),trihexyphenidyl hydrochloride (CAS-144-11-6), pirenzepine(CAS-29868-97-1), telenzepine (CAS-80880-90-9), AF-DX 116, ormethoctramine, and the compounds disclosed in WO01/04118, the disclosureof which is hereby incorporated by reference.

[0332] Suitable antihistamines (also referred to as H,-receptorantagonists) include any one or more of the numerous antagonists knownwhich inhibit HI-receptors, and are safe for human use. All arereversible, competitive inhibitors of the interaction of histamine withH₁-receptors. The majority of these inhibitors, mostly first generationantagonists, are characterized, based on their core structures, asethanolamines, ethylenediamines, and alkylamines. In addition, otherfirst generation antihistamines include those which can be characterizedas based on piperizine and phenothiazines. Second generationantagonists, which are non-sedating, have a similar structure-activityrelationship in that they retain the core ethylene group (thealkylamines) or mimic a tertiary amine group with piperizine orpiperidine. Exemplary antagonists are as follows:

[0333] Ethanolamines: carbinoxamine maleate, clemastine fumarate,diphenylhydramine hydrochloride, and dimenhydrinate.

[0334] Ethylenediamines: pyrilamine amleate, tripelennamine HCl, andtripelennamine citrate.

[0335] Alkylamines: chlropheniramine and its salts such as the maleatesalt, and acrivastine.

[0336] Piperazines: hydroxyzine HCl, hydroxyzine pamoate, cyclizine HCl,cyclizine lactate, meclizine HCl, and cetirizine HCl.

[0337] Piperidines: Astemizole, levocabastine HCl, loratadine or itsdescarboethoxy analogue, and terfenadine and fexofenadine hydrochlorideor another pharmaceutically acceptable salt.

[0338] Azelastine hydrochloride is yet another H₁ receptor antagonistwhich may be used in combination with a compound of the invention.

[0339] Examples of preferred anti-histamines include methapyrilene andloratadine.

[0340] The invention thus provides, in a further aspect, a combinationcomprising a compound of formula (I) or a pharmaceutically acceptablesalt or solvate or stereoisomer thereof and a corticosteroid. Inparticular, the invention provides a combination wherein thecorticosteroid is fluticasone propionate or wherein the coricosteroid is6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester or6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3S-yl) ester.

[0341] The invention thus provides, in a further aspect, a combinationcomprising a compound of formula (I) or a pharmaceutically acceptablesalt or solvate or stereoisomer thereof and a PDE4 inhibitor.

[0342] The invention thus provides, in a further aspect, a combinationcomprising a compound of formula (I) or a pharmaceutically acceptablesalt or solvate or stereoisomer thereof and an anticholinergic agent.

[0343] The invention thus provides, in a further aspect, a combinationcomprising a compound of formula (I) or a pharmaceutically acceptablesalt or solvate or stereoisomer thereof and an antihistamine.

[0344] The invention thus provides, in a further aspect, a combinationcomprising a compound of formula (I) or a pharmaceutically acceptablesalt or solvate or stereoisomer thereof together with a PDE4 inhibitorand a corticosteroid.

[0345] The invention thus provides, in a further aspect, a combinationcomprising a compound of formula (I) or a pharmaceutically acceptablesalt or solvate or stereoisomer thereof together with an anticholinergicagent and a corticosteroid.

[0346] As used in the above combinations, the term, “a compound offormula (I)” includes a compound of the preferred, more preferred, ormost preferred subgroup of compounds of formula (I), including acompound of formula (IIa) or (IIb) and subgroups thereof, and anyindividually disclosed compound or compounds.

[0347] Accordingly, the pharmaceutical compositions of the invention canoptionally comprise combinations of a compound of formula (I) or apharmaceutically acceptable salt or solvate or stereoisomer thereof withone or more other therapeutic agents, as described above.

[0348] The individual compounds of such combinations may be administeredeither sequentially or simultaneously in separate or combinedpharmaceutical formulations. Appropriate doses of known therapeuticagents will be readily appreciated by those skilled in the art.

[0349] According to a further aspect, the invention provides a method oftreating a disease or condition associated with β₂ adrenergic receptoractivity in a mammal, comprising administering to the mammal atherapeutically effective amount of a combination of a compound offormula (I) or a pharmaceutically acceptable salt or solvate orstereoisomer thereof with one or more other therapeutic agents.

[0350] Additional suitable carriers for formulations of the activecompounds of the present invention can be found in Remington: TheScience and Practice of Pharmacy, 20th Edition, Lippincott Williams &Wilkins, Philadelphia, Pa., 2000. The following non-limiting examplesillustrate representative pharmaceutical compositions of the invention.

FORMULATION EXAMPLE A

[0351] This example illustrates the preparation of a representativepharmaceutical composition for oral administration of a compound of thisinvention: Ingredients Quantity per tablet, (mg) Active Compound 2Lactose, spray-dried 148 Magnesium stearate 2

[0352] The above ingredients are mixed and introduced into a hard-shellgelatin capsule.

FORMULATION EXAMPLE B

[0353] This example illustrates the preparation of anotherrepresentative pharmaceutical composition for oral administration of acompound of this invention: Ingredients Quantity per tablet, (mg) ActiveCompound 4 Cornstarch 50 Lactose 145 Magnesium stearate 5

[0354] The above ingredients are mixed intimately and pressed intosingle scored tablets.

FORMULATION EXAMPLE C

[0355] This example illustrates the preparation of a representativepharmaceutical composition for oral administration of a compound of thisinvention.

[0356] An oral suspension is prepared having the following composition.Ingredients Active Compound 0.1 g Fumaric acid 0.5 g Sodium chloride 2.0g Methyl paraben 0.1 g Granulated sugar 25.5 g Sorbitol (70% solution)12.85 g Veegum K (Vanderbilt Co.) 1.0 g Flavoring 0.035 mL Colorings 0.5mg Distilled water q.s. to 100 mL

FORMULATION EXAMPLE D

[0357] This example illustrates the preparation of a representativepharmaceutical composition containing a compound of this invention.

[0358] An injectable preparation buffered to a pH of 4 is preparedhaving the following composition: Ingredients Active Compound 0.2 gSodium Acetate Buffer Solution (0.4 M) 2.0 mL HCl (1 N) q.s. to pH 4Water (distilled, sterile) q.s. to 20 mL

FORMULATION EXAMPLE E

[0359] This example illustrates the preparation of a representativepharmaceutical composition for injection of a compound of thisinvention.

[0360] A reconstituted solution is prepared by adding 20 mL of sterilewater to 1 g of the compound of this invention. Before use, the solutionis then diluted with 200 mL of an intravenous fluid that is compatiblewith the active compound. Such fluids are chosen from 5% dextrosesolution, 0.9% sodium chloride, or a mixture of 5% dextrose and 0.9%sodium chloride. Other examples are lactated Ringer's injection,lactated Ringer's plus 5% dextrose injection, Normosol-M and 5%dextrose, Isolyte E, and acylated Ringer's injection.

FORMULATION EXAMPLE F

[0361] This example illustrates the preparation of a representativepharmaceutical composition containing a compound of this invention.

[0362] An injectable preparation is prepared having the followingcomposition: Ingredients Active Compound 0.1-5.0 gHydroxypropyl-β-cyclodextrin    1-25 g 5% Aqueous Dextrose Solution(sterile) q.s. to 100 mL

[0363] The above ingredients are blended and the pH is adjusted to3.5±0.5 using 0.5 N HCl or 0.5 N NaOH.

FORMULATION EXAMPLE G

[0364] This example illustrates the preparation of a representativepharmaceutical composition for topical application of a compound of thisinvention. Ingredients grams Active compound 0.2-10 Span 60   2 Tween 60  2 Mineral oil   5 Petrolatum   10 Methyl paraben 0.15 Propyl paraben0.05 BHA (butylated hydroxy anisole) 0.01 Water q.s. to 100

[0365] All of the above ingredients, except water, are combined andheated to 60° C. with stirring. A sufficient quantity of water at 60° C.is then added with vigorous stirring to emulsify the ingredients, andwater then added q.s. 100 g.

FORMULATION EXAMPLE H

[0366] This example illustrates the preparation of a representativepharmaceutical composition containing a compound of the invention.

[0367] An aqueous aerosol formulation for use in a nebulizer is preparedby dissolving 0.1 mg of a pharmaceutical salt of active compound in a0.9% sodium chloride solution acidified with citric acid. The mixture isstirred and sonicated until the active salt is dissolved. The pH of thesolution is adjusted to a value in the range of from 3 to 8 by the slowaddition of NaOH.

FORMULATION EXAMPLE I

[0368] This example illustrates the preparation of a dry powderformulation containing a compound of the invention for use in inhalationcartridges.

[0369] Gelatin inhalation cartridges are filled with a pharmaceuticalcomposition having the following ingredients: Ingredients mg/cartridgePharmaceutical salt of active compound 0.2 Lactose 25

[0370] The pharmaceutical salt of active compound is micronized prior toblending with lactose. The contents of the cartridges are administeredusing a powder inhaler.

FORMULATION EXAMPLE J

[0371] This example illustrates the preparation of a dry powderformulation containing a compound of the invention for use in a drypowder inhalation device.

[0372] A pharmaceutical composition is prepared having a bulkformulation ratio of micronized pharmaceutical salt to lactose of 1:200.The composition is packed into a dry powder inhalation device capable ofdelivering between about 10 μg and about 100 μg of active drugingredient per dose.

FORMULATION EXAMPLE K

[0373] This example illustrates the preparation of a formulationcontaining a compound of the invention for use in a metered doseinhaler.

[0374] A suspension containing 5% pharmaceutical salt of activecompound, 0.5% lecithin, and 0.5% trehalose is prepared by dispersing 5g of active compound as micronized particles with mean size less than 10μm in a colloidal solution formed from 0.5 g of trehalose and 0.5 g oflecithin dissolved in 100 mL of demineralized water. The suspension isspray dried and the resulting material is micronized to particles havinga mean diameter less than 1.5 μm. The particles are loaded intocanisters with pressurized 1,1,1,2-tetrafluoroethane.

FORMULATION EXAMPLE L

[0375] This example illustrates the preparation of a formulationcontaining a compound of the invention for use in a metered doseinhaler.

[0376] A suspension containing 5% pharmaceutical salt of active compoundand 0.1% lecithin is prepared by dispersing 10 g of active compound asmicronized particles with mean size less than 10 μm in a solution formedfrom 0.2 g of lecithin dissolved in 200 mL of demineralized water. Thesuspension is spray dried and the resulting material is micronized toparticles having a mean diameter less than 1.5 μm. The particles areloaded into canisters with pressurized1,1,1,2,3,3,3-heptafluoro-n-propane.

[0377] Biological Assays

[0378] The compounds of this invention, and theirpharmaceutically-acceptable salts, exhibit biological activity and areuseful for medical treatment. The ability of a compound to bind to theβ₂ adrenergic receptor, as well as its selectivity, agonist potency, andintrinsic activity can be demonstrated using in vitro Tests A-C below,in vivo Test D, below, or can be demonstrated using other tests that areknown in the art. Abbreviations % Eff % efficacy ATCC American TypeCulture Collection BSA Bovine Serum Albumin cAMP Adenosine 3′:5′-cyclicmonophosphate DMEM Dulbecco's Modified Eagle's Medium DMSO Dimethylsulfoxide EDTA Ethylenediaminetetraacetic acid Emax maximal efficacy FBSFetal bovine serum Gly Glycine HEK-293 Human embryonic kidney-293 PBSPhosphate buffered saline rpm rotations per minute TrisTris(hydroxymethyl)aminomethane

Membrane Preparation From Cells Expressing Human β₁ or β₂ AdrenergicReceptors

[0379] HEK-293 derived cell lines stably expressing cloned human β₁ orβ₂ adrenergic receptors, respectively, were grown to near confluency inDMEM with 10% dialyzed FBS in the presence of 500 μg/mL Geneticin. Thecell monolayer was lifted with Versene 1:5,000 (0.2 g/L EDTA in PBS)using a cell scraper. Cells were pelleted by centrifugation at 1,000rpm, and cell pellets were either stored frozen at −80° C. or membraneswere prepared immediately. For preparation, cell pellets wereresuspended in lysis buffer (10 mM Tris/HCL pH 7.4@4° C., one tablet of“Complete Protease Inhibitor Cocktail Tablets with 2 mM EDTA” per 50 mLbuffer (Roche cat.# 1697498, Roche Molecular Biochemicals, Indianapolis,Ind.)) and homogenized using a tight-fitting Dounce glass homogenizer(20 strokes) on ice. The homogenate was centrifuged at 20,000×g, thepellet was washed once with lysis buffer by resuspension andcentrifugation as above. The final pellet was resuspended in membranebuffer (75 mM Tris/HCl pH 7.4, 12.5 mM MgCl₂, 1 mM EDTA @ 25° C.).Protein concentration of the membrane suspension was determined by themethod of Bradford (Bradford MM., Analytical Biochemistry, 1976, 72,248-54). Membranes were stored frozen in aliquots at −80° C.

Test A Radioligand Binding Assay on Human β₁ and β₂ Adrenergic Receptors

[0380] Binding assays were performed in 96-well microtiter plates in atotal assay volume of 100 μL with 5 μg membrane protein for membranescontaining the human β₂ adrenergic receptor, or 2.5 μg membrane proteinfor membranes containing the human β₁ adrenergic receptor in assaybuffer (75 mM Tris/HCl pH 7.4@25° C., 12.5 mM MgCl₂, 1 mM EDTA, 0.2%BSA). Saturation binding studies for determination of K_(d) values ofthe radioligand were done using [³H]dihydroalprenolol (NET-720, 100Ci/mmol, PerkinElmer Life Sciences Inc., Boston, Mass.) at 10 differentconcentrations ranging from 0.01 nM-200 nM. Displacement assays fordetermination of pK_(i) values of compounds were done with[³H]dihydroalprenolol at 1 nM and 10 different concentrations ofcompound ranging from 40 μM-10 μM. Compounds were dissolved to aconcentration of 10 mM in dissolving buffer (25 mM Gly-HCl pH 3.0 with50% DMSO), then diluted to 1 mM in 50 mM Gly-HCl pH 3.0, and from thereserially diluted into assay buffer. Non-specific binding was determinedin the presence of 10 μM unlabeled alprenolol. Assays were incubated for90 minutes at room temperature, binding reactions were terminated byrapid filtration over GF/B glass fiber filter plates (Packard BioScienceCo., Meriden, Conn.) presoaked in 0.3% polyethyleneimine. Filter plateswere washed three times with filtration buffer (75 mM Tris/HCl pH 7.4@4°C., 12.5 mM MgCl₂, 1 mM EDTA) to remove unbound radioactivity. Plateswere dried, 50 μL Microscint-20 liquid scintillation fluid (PackardBioScience Co., Meriden, Conn.) was added and plates were counted in aPackard Topcount liquid scintillation counter (Packard BioScience Co.,Meriden, Conn.). Binding data were analyzed by nonlinear regressionanalysis with the GraphPad Prism Software package (GraphPad Software,Inc., San Diego, Calif.) using the 3-parameter model for one-sitecompetition. The curve minimum was fixed to the value for nonspecificbinding, as determined in the presence of 10 μM alprenolol. K_(i) valuesfor compounds were calculated from observed IC₅₀ values and the K_(d)value of the radioligand using the Cheng-Prusoff equation (Cheng Y, andPrusoff W H., Biochemical Pharmacology, 1973, 22, 23, 3099-108). Thereceptor subtype selectivity was calculated as the ratio ofK_(i)(β₁)/K_(i)(β₂). All of the compounds tested demonstrated greaterbinding at the β₂ adrenergic receptor than at the β₁ adrenergicreceptor, i.e. K_(i)(β₁)>K_(i)(β₂). Most preferred compounds of theinvention demonstrated a selectivity greater than about 20.

Test B Whole-Cell cAMP Flashplate Assay With a Cell Line HeterologouslyExpressing Human β₂ Adrenergic Receptor

[0381] For the determination of agonist potencies, a HEK-293 cell linestably expressing cloned human β₂ adrenergic receptor (clone H24.14) wasgrown to confluency in medium consisting of DMEM supplemented with 10%FBS and 500 μg/mL Geneticin. The day before the assay, antibiotics wereremoved from the growth-medium.

[0382] cAMP assays were performed in a radioimmunoassay format using theFlashplate Adenylyl Cyclase Activation Assay System with ¹²⁵I-cAMP (NENSMP004, PerkinElmer Life Sciences Inc., Boston, Mass.), according to themanufacturers instructions.

[0383] On the day of the assay, cells were rinsed once with PBS, liftedwith Versene 1:5,000 (0.2 g/L EDTA in PBS) and counted. Cells werepelleted by centrifugation at 1,000 rpm and resuspended in stimulationbuffer prewarmed to 37° C. at a final concentration of 800,000 cells/mL.Cells were used at a final concentration of 40,000 cells/well in theassay. Compounds were dissolved to a concentration of 10 mM indissolving buffer (25 mM Gly-HCl pH 3.0 with 50% DMSO), then diluted to1 mM in 50 mM Gly-HCl pH 3.0, and from there serially diluted into assaybuffer (75 mM Tris/HCl pH 7.4@25° C., 12.5 mM MgCl₂, 1 mM EDTA, 0.2%BSA). Compounds were tested in the assay at 10 different concentrations,ranging from 2.5 FM to 9.5 pM. Reactions were incubated for 10 min at37° C. and stopped by addition of 100 ill ice-cold detection buffer.Plates were sealed, incubated over night at 4° C. and counted the nextmorning in a topcount scintillation counter (Packard BioScience Co.,Meriden, Conn.). The amount of cAMP produced per mL of reaction wascalculated based on the counts observed for the samples and cAMPstandards, as described in the manufacturer's user manual. Data wereanalyzed by nonlinear regression analysis with the GraphPad PrismSoftware package (GraphPad Software, Inc., San Diego, Calif.) using the4-parameter model for sigmoidal dose-response with variable slope.Agonist potencies were expressed as pEC₅₀ values. All of the compoundstested demonstrated activity at the β₂ adrenergic receptor in thisassay, as evidenced by pEC₅₀ values greater than about 5. Most preferredcompounds of the invention demonstrated pEC₅₀ values greater than about7.

Test C Whole-Cell cAMP Flashplate Assay With a Lung Epithelial Cell LineEndogenously Expressing Human 032 Adrenergic Receptor

[0384] For the determination of agonist potencies and efficacies(intrinsic activities) in a cell line expressing endogenous levels of β₂adrenergic receptor, a human lung epithelial cell line (BEAS-2B) wasused (ATCC CRL-9609, American Type Culture Collection, Manassas, Va.)(January B, et al., British Journal of Pharmacology, 1998, 123, 4,701-11). Cells were grown to 75-90% confluency in complete, serum-freemedium (LHC-9 MEDIUM containing Epinephrine and Retinoic Acid, cat #181-500, Biosource International, Camarillo, Calif.). The day before theassay, medium was switched to LHC-8 (No epinephrine or retinoic acid,cat # 141-500, Biosource International, Camarillo, Calif.). cAMP assayswere performed in a radioimmunoassay format using the FlashplateAdenylyl Cyclase Activation Assay System with ¹²⁵I-cAMP (NEN SMP004,PerkinElmer Life Sciences Inc., Boston, Mass.), according to themanufacturers instructions. On the day of the assay, cells were rinsedwith PBS, lifted by scraping with 5mM EDTA in PBS, and counted. Cellswere pelleted by centrifugation at 1,000 rpm and resuspended instimulation buffer prewarmed to 37° C. at a final concentration of600,000 cells/mL. Cells were used at a final concentration of 30,000cells/well in the assay. Compounds were dissolved to a concentration of10 mM in dissolving buffer (25 mM Gly-HCl pH 3.0 with 50% DMSO), thendiluted to 1 mM in 50 mM Gly-HCl pH 3.0, and from there serially dilutedinto assay buffer (75 mM Tris/HCl pH 7.4@25° C., 12.5 mM MgCl₂, 1 mMEDTA, 0.2% BSA).

[0385] Compounds were tested in the assay at 10 differentconcentrations, ranging from 10 μM to 40 pM. Maximal response wasdetermined in the presence of 10 μM Isoproterenol. Reactions wereincubated for 10 min at 37° C. and stopped by addition of 100 μlice-cold detection buffer. Plates were sealed, incubated over night at4° C. and counted the next morning in a topcount scintillation counter(Packard BioScience Co., Meriden, Conn.). The amount of cAMP producedper mL of reaction was calculated based on the counts observed forsamples and cAMP standards, as described in the manufacturer's usermanual. Data were analyzed by nonlinear regression analysis with theGraphPad Prism Software package (GraphPad Software, Inc., San Diego,Calif.) using the 4-parameter model for sigmoidal dose-response withvariable slope. Compounds of the invention tested in this assaydemonstrated pEC₅₀ values greater than about 7.

[0386] Compound efficacy (%Eff) was calculated from the ratio of theobserved Emax (TOP of the fitted curve) and the maximal responseobtained for 10 μM isoproterenol and was expressed as %Eff relative toisoproterenol. The compounds tested demonstrated a %Eff greater thanabout 20.

Test D Assay of Bronchoprotection Against Acetylcholine-InducedBronchospasm in a Guinea Pig Model

[0387] Groups of 6 male guinea pigs (Duncan-Hartley (HsdPoc:DH) Harlan,Madison, Wis.) weighing between 250 and 350 g were individuallyidentified by cage cards. Throughout the study animals were allowedaccess to food and water ad libitum.

[0388] Test compounds were administered via inhalation over 10 minutesin a whole-body exposure dosing chamber (R&S Molds, San Carlos, Calif.).The dosing chambers were arranged so that an aerosol was simultaneouslydelivered to 6 individual chambers from a central manifold. Following a60 minute acclimation period and a 10 minute exposure to nebulized waterfor injection (WFI), guinea pigs were exposed to an aerosol of testcompound or vehicle (WFI). These aerosols were generated from aqueoussolutions using an LC Star Nebulizer Set (Model 22F51, PARI RespiratoryEquipment, Inc. Midlothian, Va.) driven by a mixture of gases (CO₂=5%,02=21% and N₂=74%) at a pressure of 22 psi. The gas flow through thenebulizer at this operating pressure was approximately 3 L/minute. Thegenerated aerosols were driven into the chambers by positive pressure.No dilution air was used during the delivery of aerosolized solutions.During the 10 minute nebulization, approximately 1.8 mL of solution wasnebulized. This was measured gravimetrically by comparing pre-andpost-nebulization weights of the filled nebulizer.

[0389] The bronchoprotective effects of compounds administered viainhalation were evaluated using whole body plethysmography at 1.5, 24,48 and 72 hours post-dose. Forty-five minutes prior to the start of thepulmonary evaluation, each guinea pig was anesthetized with anintramuscular injection of ketamine (43.75 mg/kg), xylazine (3.50 mg/kg)and acepromazine (1.05 mg/kg). After the surgical site was shaved andcleaned with 70% alcohol, a 2-5 cm midline incision of the ventralaspect of the neck was made. Then, the jugular vein was isolated andcannulated with a saline-filled polyethylene catheter (PE-50, BectonDickinson, Sparks, Md.) to allow for intravenous infusions of a 0.1mg/mL solution of acetylcholine (Ach), (Sigma-Aldrich, St. Louis, Mo.)in saline. The trachea was then dissected free and cannulated with a 14Gteflon tube (#NE-014, Small Parts, Miami Lakes, Fla.). If required,anesthesia was maintained by additional intramuscular injections of theaforementioned anesthetic cocktail. The depth of anesthesia wasmonitored and adjusted if the animal responded to pinching of its paw orif the respiration rate was greater than 100 breaths/minute.

[0390] Once the cannulations were complete, the animal was placed into aplethysmograph (#PLY3114, Buxco Electronics, Inc., Sharon, Conn.) and anesophageal pressure cannula was inserted to measure pulmonary drivingpressure (pressure). The teflon tracheal tube was attached to theopening of the plethysmograph to allow the guinea pig to breathe roomair from outside the chamber. The chamber was then sealed. A heatinglamp was used to maintain body temperature and the guinea pig's lungswere inflated 3 times with 4 mL of air using a 10 mL calibration syringe(#5520 Series, Hans Rudolph, Kansas City, Mo.) to ensure that the lowerairways had not collapsed and that the animal did not suffer fromhyperventilation.

[0391] Once it was determined that baseline values were within the range0.3-0.9 mL/cm H₂O for compliance and within the range 0.1-0.199 cmH₂O/nL per second for resistance, the pulmonary evaluation wasinitiated. A Buxco pulmonary measurement computer progam enabled thecollection and derivation of pulmonary values. Starting this programinitiated the experimental protocol and data collection. The changes involume over time that occured within the plethysmograph with each breathwere measured via a Buxco pressure transducer. By integrating thissignal over time, a measurement offiow was calculated for each breath.This signal, together with the pulmonary driving pressure changes, whichwere collected using a Sensym pressure transducer (#TRD4T00), wasconnected via a Buxco (MAX 2270) preamplifier to a data collectioninterface (#'s SFT3400 and SFT3813). All other pulmonary parameters werederived from these two inputs.

[0392] Baseline values were collected for 5 minutes, after which timethe guinea pigs were challenged with Ach. Ach was infused intravenouslyfor 1 minute from a syringe pump (sp210iw, World Precision Instruments,Inc., Sarasota, Fla.) at the following doses and prescribed times fromthe start of the experiment: 1.9 μg/minute at 5 minutes, 3.8 μg/minuteat 10 minutes, 7.5 μg/minute at 15 minutes, 15.0 μg/minute at 20minutes, 30 μg/minute at 25 minutes and 60 μg/minute at 30 minutes. Ifresistance or compliance had not returned to baseline values at 3minutes following each Ach dose, the guinea pig's lungs were inflated 3times with 4 mL of air from a 10 mL calibration syringe. Recordedpulmonary parameters included respiration frequency (breaths/minute),compliance (mL/cm H₂O) and pulmonary resistance (cm H₂O/nL per second)(Giles et al., 1971). Once the pulmonary function measurements werecompleted at minute 35 of this protocol, the guinea pig was removed fromthe plethysmograph and euthanized by CO₂ asphyxiation.

[0393] The quantity PD₂, which is defined as the amount of Ach needed tocause a doubling of the baseline pulmonary resistance, was calculatedusing the pulmonary resistance values derived from the flow and thepressure over a range of Ach challenges using the following equation.This was derived from the equation used to calculate PC₂₀ values in theclinic (Am. Thoracic Soc, 2000).${PD}_{2} = {{antilog}\left\lbrack {{\log \quad C_{1}} + \frac{\left( {{\log \quad C_{2}} - {\log \quad C_{1}}} \right)\left( {{2R_{0}} - R_{1}} \right)}{R_{2} - R_{1}}} \right\rbrack}$

[0394] where:

[0395] C₁=Second to last Ach concentration (concentration preceding C₂)

[0396] C₂=Final concentration of Ach (concentration resulting in a2-fold increase in pulmonary resistance (R_(L)))

[0397] R₀=Baseline R_(L) value

[0398] R₁=R_(L) value after C₁

[0399] R₂=R_(L) value after C₂

[0400] Statistical analysis of the data was performed using a One-WayAnalysis of Variance followed by post-hoc analysis using aBonferroni/Dunn test. A P-value <0.05 was considered significant.

[0401] Dose-response curves were fitted with a four parameter logisticequation using GraphPad Prism, version 3.00 for Windows (GraphPadSoftware, San Diego, Calif.)

Y=Min+(Max−Min)/(1+10{circumflex over ( )}((log ED ₅₀ −X)*Hillslope)),

[0402] where X is the logarithm of dose, Y is the response (PD₂), and Ystarts at Min and approaches asymptotically to Max with a sigmoidalshape.

[0403] Representative compounds of the invention were found to havesignificant bronchoprotective activity at time points beyond 24 hourspost-dose.

[0404] The following synthetic examples are offered to illustrate theinvention, and are not to be construed in any way as limiting the scopeof the invention.

EXAMPLES

[0405] In the examples below, the following abbreviations have thefollowing meanings. Any abbreviations not defined have their generallyaccepted meaning. Unless otherwise stated, all temperatures are indegrees Celsius. Bn = benzyl Boc = tert-butoxycarbonyl DMSO = dimethylsulfoxide EtOAc = ethyl acetate TFA = trifluoroacetic acid THF =tetrahydrofuran MgSO₄ = anhydrous magnesium sulfate NaHMDS = sodiumhexamethyldisilazane TMSCl = trimethylsilyl chloride DMF = dimethylformamide Boc = tert-butoxycarbonyl TBS = tert-butyldimethylsilyl

[0406] General: Unless noted otherwise, reagents, starting material andsolvents were purchased from commercial suppliers, for exampleSigma-Aldrich (St. Louis, Mo.), J. T. Baker (Phillipsburg, N.J.),Honeywell Burdick and Jackson (Muskegon, Mich.), Trans World Chemicals,Inc. (TCI) (Rockville, Md.), Mabybridge plc (Cornwall, UK), PeakdaleMolecular Limited (High Peak, UK), Avocado Research Chemicals Limited(Lancashire, UK), and Bionet Research (Cornwall, UK) and used withoutfurther purification; reactions were run under nitrogen atmosphere;reaction mixtures were monitored by thin layer chromatography (silicaTLC), analytical high performance liquid chromatography (anal. HPLC), ormass spectrometry; reaction mixtures were commonly purified by flashcolumn chromatography on silica gel, or by preparative HPLC as describedbelow; NMR samples were dissolved in deuterated solvent (CD₃OD, CDCl₃,or DMSO-d6), and spectra were acquired with a Varian Gemini 2000instrument (300 MHz) using the residual protons of the listed solvent asthe internal standard unless otherwise indicated; and mass spectrometricidentification was performed by an electrospray ionization method (ESMS)with a Perkin Elmer instrument (PE SCIEX API 150 EX).

Example 1 Synthesis of Compound 1

[0407]

[0408] To 62 mg (0.1 mmol) of compound bb and 0.1 mmol ofN′-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide (available fromSigma-Aldrich Library of Rare Chemicals) 0.15 mL of toluene were added9.3 mg (0.015 mmol) ofracemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (Aldrich) in 0.15 mLtoluene, 4.6 mg (0.05 mmol) of tris(dibenzylidineacetone)dipalladium(0)(Aldrich) in 0.1 mL toluene, and 29 mg (0.3 mmol) of sodiumtert-butoxide slurried in 0.4 mL toluene. The mixture was shaken andheated at 80° C. for 5 hours. Acetic acid (80% aq., 0.6 mL) was addedand the mixture was shaken and heated at 80° C. for 5 hours. The crudereaction was diluted to a total volume of 2 mL with DMF, filtered, andpurified by reversed phase HPLC, using a mass-triggered, automatedcollection device. The product containing fractions were analyzed byanalytical LC-MS, and freeze-dried to give a TFA salt of compound 1 as apowder.

[0409] The intermediate compound bb was prepared as follows.

[0410] a. Synthesis of Compound xx.

[0411] To 5-bromo-2-hydroxybenzyl alcohol (93 g, 0.46 mol, availablefrom Aldrich) in 2.0 L of 2,2-dimethoxypropane was added 700 mL ofacetone, followed by 170 g of ZnCl₂. After stirring for 18 hours, 1.0 Maqueous NaOH was added until the aqueous phase was basic. 1.5 L ofdiethyl ether was added to the slurry, and the organic phase wasdecanted into a seporatory funnel. The organic phase was washed withbrine, dried over Na₂SO₄, filtered, and concentrated under reducedpressure to give compound xx as a light orange oil. ¹H NMR (300 MHz,DMSO-d6) δ 7.28 (m, 2H), 6.75 (d, 1H), 4.79 (s, 2H), 1.44 (s, 6H).

[0412] b. Synthesis of Compound yy

[0413] To 110 g (0.46 mol) of compound xx in 1.0 L of THF at −78° C. wasadded 236 mL (0.51 mol) of 2.14 M n-BuLi in hexanes via a droppingfunnel. After 30 minutes, 71 g (0.69 mol) of N-Methyl-N-methoxyacetamide(available from TCI) was added. After 2 hours, the reaction was quenchedwith water, diluted with 2.0 L of 1.0 M aqueous phosphate buffer(pH=7.0), and extracted once with diethyl ether. The diethyl ether phasewas washed once with brine, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure to give a light orange oil. The oilwas dissolved in a minimum volume of ethyl acetate, diluted withhexanes, and the product crystallized to give compound yy as a whitesolid. ¹H NMR (300 MHz, CDCl₃) δ 7.79 (m, 1H), 7.65 (m, 1H), 6.85 (d,1H), 4.88 (s, 2H), 2.54 (s, 3H), 1.56 (s, 6H).

[0414] c. Synthesis of Compound zz.

[0415] To 23.4 g (0.113 mol) of compound yy in 600 mL of THF at −78° C.was added 135 mL of 1.0 M NaHMDS in THF (Aldrich). After 1 hour, 15.8 mL(0.124 mol) of TMSCl was added. After another 30 minutes, 5.82 mL (0.113mol) of bromine was added. After a final 10 minutes, the reaction wasquenched by diluting with diethyl ether and pouring onto 500 mL of 5%aqueous Na₂SO₃ premixed with 500 mL of 5% aqueous NaHCO₃. The phaseswere separated, and the organic phase was washed with brine, dried overNa₂SO₄, filtered, and concentrated under reduced pressure to givecompound zz as a light orange oil that solidified in the freezer. ¹H NMR(300 MHz, CDCl₃) δ 7.81 (m, 1H), 7.69 (m, 1H), 6.88 (d, 1H), 4.89 (s,2H), 4.37 (s, 2H), 1.56 (s, 6H).

[0416] d. Synthesis of Compound aa.

[0417] To 32 g (0.113 mol) of compound zz in 300 mL methylene chlorideat 0° C. was added 31.6 mL (0.23 mol) of triethylamine, followed by 16.0mL (0.10 mol) of4-bromophenethylamine (Aldrich). After 2 hours, 27 g(0.10 mol) of the 4,4′-dimethoxychlorodiphenylmethane was added. After30 minutes, the slurry was partitioned between 50% saturated aqueousNaHCO₃ and diethyl ether, and the phases were separated. The organicphase was washed once each with water and brine, dried over K₂CO₃,filtered, and concentrated to an orange oil. The oil was purified bysilica gel chromatography (1400 L silica gel, eluted with 3acetonitrile/0.5 triethylamine/96.5 methylene chloride) to give compoundaa as a light orange foam. ¹H NMR (300 MHz, DMSO-d6) δ 7.65 (m, 1H),7.57 (m, 1H), 7.38 (d, 2H), 7.19 (d, 4H), 6.95 (d, 2H), 6.78 (m, 5H),5.09 (s, 1H), 4.82 (s, 2H), 3.98 (s, 2H), 3.73 (m, 1H), 3.66 (s, 6H),2.71 (m, 4H), 1.45 (s, 6H).

[0418] e. Synthesis of Compound bb.

[0419] To 41 g (65 mmol) of compound aa in 120 mL of THF was added 200mL of methanol, followed by 2.46 g (65 mmol) of sodium borohydride.After 1 hour, the solution was partitioned between 1.0 M aqueousphosphate buffer (pH=7.0) and diethyl ether, and the phases wereseparated. The diethyl ether phase was washed with brine, dried overK₂CO₃, filtered, and concentrated to an oil. The oil was purified bysilica gel chromatography (1200 mL silica gel, eluted with 18acetone/0.5 triethylamine/81.5 hexanes) to give compound bb as a whitefoam. ¹H NMR (300 MHz, DMSO-d6) δ 7.37 (d, 2H), 7.13 (m, 4H), 6.95-6.75(m, 8H), 6.68 (d, 1H), 4.95 (d, 1H), 4.83 (s, 1H), 4.74 (s, 2H), 4.56(m, 1H), 3.67 (2, 6H), 2.55 (m, 4H), 1.42 (s, 6H).

Example 2 Synthesis of Compound 2

[0420]

[0421] Using a coupling procedure similar to that described in Example1, except replacing the N-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamidewith N′-(5-methoxy-2-pyrimidinyl)sulfanilamide (sulfameter, availablefrom Aldrich), a TFA salt of compound 2 was prepared. m/z: [M+H⁺] calcdfor C₂₈H₃₁N₅O₆S 566.2; found 566.2.

Example 3 Synthesis of Compound 3

[0422]

[0423] Using a coupling procedure similar to that described in Example1, except replacing theN′-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide withN′-(4,6-dimethyl-2-pyrimidinyl)sulfanylamide (sulfamethazine, availablefrom Aldrich), a TFA salt of compound 3 was prepared. m/z: [M+H⁺] calcdfor C₂₉H₃₃N₅O₅S 564.2; found 564.2.

Example 4 Synthesis of Compound 4

[0424]

[0425] Using a coupling procedure similar to that described in Example1, except replacing theN¹-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide with2-sulfanilamidopyrimidine (sulfapyridine, available from Aldrich), a TFAsalt of compound 4 was prepared. m/z: [M+H⁺] calcd for C₂₈H₃₀N₄O₅S535.2; found 535.2.

Example 5 Synthesis of Compound 5

[0426]

[0427] Using a coupling procedure similar to that described in Example1, except replacing theN′-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide with5-amino-ortho-toluenesulfonanilide (p-toluidine-o-sulfanilide, availablefrom Sigma-Aldrich Library of Rare Chemicals), a TFA salt of compound 5was prepared. m/z: [M+H⁺] calcd for C₃₀H₃₃N₃O₅S 548.2; found 548.2.

Example 6 Synthesis of Compound 6

[0428]

[0429] Using a coupling procedure similar to that described in Example1, except replacing theN¹-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide with4-aminotoluene-2-sulfethylanilide (available from Sigma-Aldrich Libraryof Rare Chemicals), a TFA salt of compound 6 was prepared. m/z: [M+H⁺]calcd for C₃₂H₃₇N₃O₅S 576.3; found 576.2.

Example 7 Synthesis of Compound 7

[0430]

[0431] Using a coupling procedure similar to that described in Example1, except replacing theN′-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide with4-(piperidinosulfonyl)aniline (available from Maybridge), a TFA salt ofcompound 7 was prepared. m/z: [M+H⁺] calcd for C₂₈H₃₅N₃O₅S 526.2; found526.2.

Example 8 Synthesis of Compound 8

[0432]

[0433] Using a coupling procedure similar to that described in Example1, except replacing theN¹-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide with4-(morpholinosulfonyl)aniline (available from Maybridge), a TFA salt ofcompound 8 was prepared. m/z: [M+H⁺] calcd for C₂₇H₃₃N₃O₆S 528.2; found528.2.

Example 9 Synthesis of Compound 9

[0434]

[0435] Using a coupling procedure similar to that described in Example1, except replacing theN′-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide withN′-(2,6-dimethylphenyl)-4-aminobenzene-1-sulfonamide (available fromMaybridge), a TFA salt of compound 9 was prepared. m/z: [M+H⁺] calcd forC₃₁H₃₅N₃O₅S 562.2; found 562.2.

Example 10 Synthesis of Compound 10

[0436]

[0437] Using a coupling procedure similar to that described in Example1, except replacing theN¹-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide withN′-(2-thiazolyl)sulfanilamide (sulfathiazole, available from Aldrich), aTFA salt of compound was prepared.

Example 11 Synthesis of Compound 11

[0438]

[0439] Using a coupling procedure similar to that described in Example1, except replacing theN′-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide withN′-[2-(trifluoromethyl)phenyl]-4-aminobenzene-1-sulfonamide (availablefrom Maybridge), a TFA salt of compound 11 was prepared.

Example 12 Synthesis of Compound 12

[0440]

[0441] Using a coupling procedure similar to that described in Example1, except replacing theN¹-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide withN′-(3,5-dichlorophenyl)-4-aminobenzene-1-sulfonamide (available fromMaybridge), a TFA salt of compound 12 was prepared.

Example 13 Synthesis of Compound 13

[0442]

[0443] To a mixture of 0.69 g (1.83 mmol) of crude compound ee in 4 mLof methanol was added 70 mg of 10% palladium on carbon under a stream ofnitrogen and the reaction was shaken under 50 psi H₂ for 2 days. Thereaction was filtered and the residue was purified by reversed phaseHPLC (gradient of 10 to 50% acetonitrile in 0.1% aqueous TFA). Fractionscontaining pure product were combined and lyophilized to afford a TFAsalt of compound 13 as a powder. m/z: [M+H⁺] calcd for C₂₇H₃₂N₄O₆S541.2; found 541.5.

[0444] The intermediate compound ee was prepared as follows.

[0445] a. Synthesis of Compound A.

[0446] To 10.7 g (53.0 mmol) of 4-bromophenethylamine (available fromAldrich) in 100 mL of toluene was added 6.80 g (64 mmol) ofbenzaldehyde. After stirring for 10 minutes, the cloudy mixture wasconcentrated under reduced pressure. The residue was re-concentratedtwice from toluene, and the clear oil was dissolved in 50 mL oftetrahydrofuran. 2.0 g (53 mmol) of sodium borohydride was added to thesolution, followed by 20 mL of methanol, and the flask was stirred in awater bath at ambient temperature for one hour. 1.0 M aqueous HCl wasadded until the pH was below 1. The slurry was stirred in an ice bathfor 30 minutes, and the solids were isolated by filtration, rinsed withcold water, and air dried to give the hydrochloride salt of compound Aas a colorless solid. ¹H NMR (300 MHz, DMSO-d6) δ 9.40 (s, 2H),7.50-7.32 (m, 7H), 7.14 (d, 2H), 4.07 (s, 2H), 3.03 (m, 2H), 2.92 (m,2H).

[0447] b. Synthesis of Compound B.

[0448] To 5.0 g (15 mmol) of compound A in 100 mL of methanol was added1.70 g (16.5 mmol) of triethylamine. The solution was cooled in anice/water bath, and 3.66 g (16.8 mmol) of di-tert-butyldicarbonate wasadded. After 3.5 hours, the solution was concentrated under reducedpressure, and the residue was partitioned between 1.0 M aqueous NaHSO₄and diethyl ether, and the phases were separated. The diethyl etherphase was washed with water followed by brine, dried over Na₂SO₄,filtered, and concentrated to give compound B (6.1 g, 93%) as acolorless oil. ¹H NMR (300 MHz, DMSO-d6) δ 7.38 (d, 2H), 7.28-7.13 (m,5H), 7.04 (m, 2H), 4.29 (br s, 2H), 3.20 (m, 2H), 2.62 (m, 2H), 1.25 (s,9H).

[0449] c. Synthesis of Compound dd.

[0450] To a flask containing 3.4 g (8.8 mmol) of compound B, 2.8 g (11mmol) of 4-morpholinosulfonyl)aniline (available from Maybridge), 0.41 g(0.45 mmol) of tris(dibenzylidineacetone)dipalladium(0), 0.83 g (1.3mmol) of rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, and 1.1 g (11mmol) of sodium tert-butoxide was added 40 mL of toluene, and themixture was heated at 95° C. for 6 h under a nitrogen atmosphere. Themixture was diluted with 200 mL diethyl ether and washed twice with 100mL portions of 1.0 M aqueous NaHSO₄, followed by 100 mL of saturatedaqueous NaHCO₃. The diethyl ether phase was dried over MgSO₄, filtered,and concentrated to a dark oil. The oil was purified by silica gelchromatography (gradient of 30 to 40% ethyl acetate in hexanes) toafford compound dd as a yellow foam (2.5 g, 51%).

[0451] d. Synthesis of Compound ee.

[0452] To 0.56 g of compound dd (0.6 mmol) in 6 mL CH₂Cl₂ was added 4 mLTFA. After 15 minutes, the solution was concentrated, diluted with 30 mLethyl acetate and washed twice with 1.0 N aqueous sodium hydroxide. Theethyl acetate layer was dried over MgSO₄, filtered, and concentrated toan oil and dissolved in 8 mL of 1:1 methanol:THF. Bromohydrin GG (340mg, 0.96 mmol) and K₂CO₃ (370 mg, 2.7 mmol) were added and the reactionwas stirred at room temperature for 1.5 h. The reaction was concentratedand the residue was diluted with 30 mL water and extracted twice with 30mL portions of toluene. The toluene extracts were combined, dried overNa₂SO₄, filtered, and concentrated. The residue was heated to 120° C.After 13 h, the reaction was cooled to room temperature and the crudecompound dd was carried on to the next step without purification.

[0453] The intermediate bromohydrin GG can be prepared as described inU.S. Pat. No. 6,268,533 BI; and in R. Hett et al., Organic ProcessResearch and Development, 1998, 2, 96-99. The intermediate bromohydrinGG can also be prepared using procedures similar to those described byHong et al., Tetrahedron Lett., 1994, 35, 6631; or similar to thosedescribed in U.S. Pat. No. 5,495,054.

Example 14 Synthesis of Compound 14

[0454]

[0455] To a mixture of 0.6 g (0.83 mmol) of compound 1i in 25 mL ofethanol was added 200 mg of 10% palladium on carbon under a stream ofnitrogen and the reaction was allowed to stir under H₂ at atmosphericpressure for 5 days. The reaction was filtered and the residue waspurified by reversed phase HPLC (gradient of 10 to 50% acetonitrile in0.1% aqueous TFA). Fractions containing pure product were combined andlyophilized to afford a TFA salt of compound 14 as a powder. m/z: [M+H⁺]calcd for C₂₈H₂₉N₅O₅S 548.2; found 548.3.

[0456] The intermediate ii was prepared as follows.

[0457] a. Synthesis of Compound hh.

[0458] To a flask containing 3.4 g (8.8 mmol) of compound B (Example 13,part b), 2.0 g (8.0 mmol) of sulfapyridine (available from Aldrich),0.37 g (0.40 mmol) of tris(dibenzylidineacetone)dipalladium(0), 0.75 g(1.2 mmol) of racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, and2.31 g (24.0 mmol) of sodium tert-butoxide was added 40 mL of toluene,and the mixture was heated at 90° C. for 18 h under a nitrogenatmosphere. The mixture was diluted with 200 mL methylene chloride andwashed with 100 mL of saturated aqueous NaHCO₃, followed by 100 mLsaturated aqueous NaCl. The organic phase was dried over MgSO₄,filtered, and concentrated. The oil was purified by silica gelchromatography (gradient of 0 to 5% methanol in methylene chloride) toafford compound hh as an orange solid.

[0459] b. Synthesis of Compound ii.

[0460] To 4.5 g of compound hh (8.1 mmol) in 20 mL CH₂Cl₂ was added 1.5mL TFA. After 1 hour, the solution was concentrated, basified with 1.0 Naqueous sodium hydroxide and extracted twice with methylene chloride,followed by an extraction using ethyl acetate. The organic layers werecombined, dried over MgSO₄, filtered, and concentrated to an oil. Theoil was purified by silica gel chromatography (gradient of 2 to 10%methanol in methylene chloride). The purified product was dissolved in10 mL of 1:1 methanol:THF. Bromohydrin GG (Example 13, part d) (364 mg,1.04 mmol) and K₂CO₃ (378 mg, 2.73 mmol) were added and the reaction wasstirred at room temperature for 1.5 h. The reaction was concentrated andthe residue was diluted with 30 mL water and extracted twice with 30 mLportions of toluene. The toluene extracts were combined, dried overNa₂SO₄, filtered, and concentrated. The residue was heated to 120° C.After 2 h, the reaction was cooled to room temperature and the crudecompound was purified by silica gel chromatography (gradient of 5 to 10%methanol in methylene chloride) to afford compound 1i as a tan solid.

Example 15 Synthesis of Compound 15

[0461]

[0462] To 610 mg of compound ff (0.82 mmol) in 5.0 mL acetic acid wasadded 92 mg of 10% palladium on carbon. The reaction mixture was shakenunder 40 psi H₂ for 20 h. The mixture was filtered and the filtrate waspurified by reversed phase HPLC (gradient of 10 to 40% acetonitrile in0.1% aqueous TFA). Fractions containing pure product were combined andlyophilized to afford a TFA salt of compound 15 as a powder. m/z: [M+H⁺]calcd for C₂₉H₃₂N₄O₆S 565.2; found 565.3.

[0463] The intermediate compound ff was prepared as follows.

[0464] a. Synthesis of Compound ff.

[0465] To 0.91 g of compound dd (1.6 mmol, Example 13, part c) in 8 mLCH₂Cl₂ was added 6 mL TFA. After 15 minutes, the solution wasconcentrated, diluted with 30 nL ethyl acetate and washed twice with 1.0N aqueous sodium hydroxide. The ethyl acetate layer was dried overMgSO₄, filtered, and concentrated to a brown oil. The oil was dissolvedin 6.0 mL of isopropanol and 375 mg (1.3 mmol) of epoxide P were added.The solution was heated to 70° C. After 24 h, the solution wasconcentrated and the product purified by silica gel chromatography (3%methanol in CH₂Cl₂). Pure fractions were combined and concentrated toafford compound ff as a yellow foam.

[0466] The intermediate epoxide P can be prepared as described inInternational Patent Application Publication Number WO 95/25104; and asdescribed in EP 0 147 719 A2 and EP 0 147 791 B.

Example 16 Synthesis of Compound 16

[0467]

[0468] Using a coupling procedure similar to that described in Example1, except replacing theN¹-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide with3-(methylthio)aniline (available from Aldrich), a TFA salt of compound16 was prepared. m/z: [M+H⁺] calcd for C₂₄H₂₈N₂O₃S 425.2; found 425.1.

Example 17 Synthesis of Compound 17

[0469]

[0470] Using a coupling procedure similar to that described in Example1, except replacing theN′-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide with4-(methylthio)aniline (available from Aldrich), a TFA salt of compound17 was prepared. m/z: [M+H⁺] calcd for C₂₄H₂₈N₂O₃S 425.2; found 425.1.

Example 18 Synthesis of Compound 18

[0471]

[0472] Using a coupling procedure similar to that described in Example1, except replacing theN′-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide 4-(m-tolylthio)aniline(available from Sigma-Aldrich Library of Rare Chemicals), a TFA salt ofcompound 18 was prepared. m/z: [M+H⁺] calcd for C₃₀H₃₂N₂O₃S 501.2; found501.2.

Example 19 Synthesis of Compound 19

[0473]

[0474] Using a coupling procedure similar to that described in Example1, except replacing theN¹-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide with4-[(4-methylpyrimidin-2-yl)thio]benzeneamine (available from Peakdale),a TFA salt of compound 19 was prepared. m/z: [M+H⁺] calcd forC₂₈H₃₀N₄O₃S 503.2; found 503.1.

Example 20 Synthesis of Compound 20

[0475]

[0476] Using a coupling procedure similar to that described in Example1, except replacing theN¹-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide with4-[(4-fluorophenyl)sulfonyl]aniline (available from Bionet), a TFA saltof compound 20 was prepared.

Example 21 Synthesis of Compound 21

[0477]

[0478] Using a coupling procedure similar to that described in Example1, except replacing theN¹-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide with4-[(4-methylphenyl)sulfonyl]aniline (available from Bionet), a TFA saltof compound 21 was prepared.

Example 22 Synthesis of Compound 22

[0479]

[0480] Using a coupling procedure similar to that described in Example1, except replacing theN′-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide with 3-aminodiphenylsulfone (available from Sigma-Aldrich Library of Rare Chemicals), a TFAsalt of compound 22 was prepared. m/z: [M+H⁺] calcd for C₂₉H₃₀N₂O₅S519.2; found 519.2.

Example 23 Synthesis of compound 23

[0481]

[0482] Using a coupling procedure similar to that described in Example1, except replacing theN′-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide with4-(4-chloro-benzenesulfonyl)-phenylamine (available from Sigma-AldrichLibrary of Rare Chemicals), a TFA salt of compound 23 was prepared. m/z:[M+H⁺] calcd for C₂₉H₂₉ClN₂O₅S 553.2; found 553.1.

Example 24 Synthesis of Compound 24

[0483]

[0484] Using a coupling procedure similar to that described in Example1, except replacing theN¹-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide with4-(methylsulfonyl)aniline (available from Maybridge), a TFA salt ofcompound 24 was prepared. m/z: [M+H⁺] calcd for C₂₄H₂₈N₂O₅S 457.2; found457.1.

Example 25 Synthesis of Compound 25

[0485]

[0486] Using a coupling procedure similar to that described in Example1, except replacing theN¹-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide with4-(phenylsulfonyl)aniline (available from Maybridge), a TFA salt ofcompound 25 was prepared. m/z: [M+H⁺] calcd for C₂₉H₃₀N₂O₅S 519.2; found519.2.

Example 26 Synthesis of Compound 26

[0487]

[0488] Using a coupling procedure similar to that described in Example1, except replacing theN′-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide with4-[(4-fluorophenyl)sulfonyl]aniline (available from Maybridge), a TFAsalt of compound 26 was prepared. m/z: [M+H⁺] calcd for C₂₉H₂₉FN₂O₅S537.2; found 537.1.

Example 27 Synthesis of Compound 27

[0489]

[0490] Using a coupling procedure similar to that described in Example1, except replacing theN′-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide with3,4-ethylenedioxyaniline (available from Aldrich), a TFA salt ofcompound 27 was prepared.

Example 28 Synthesis of Compound 28

[0491]

[0492] Using a coupling procedure similar to that described in Example1, except replacing theN′-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide with 4-methoxyaniline(p-anisidine, available from Aldrich), a TFA salt of compound 28 wasprepared.

Example 29 Synthesis of Compound 29

[0493]

[0494] Using a coupling procedure similar to that described in Example1, except replacing theN¹-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide with 3-ethoxyaniline(m-anisidine, available from Aldrich), a TFA salt of compound 29 wasprepared.

Example 30 Synthesis ofN-{2-[4-(4-ethoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine(30)

[0495]

[0496] Using a coupling procedure similar to that described in Example1, except replacing theN¹-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide withl-amino-4-ethoxybenzene (p-phenetidine, available from Aldrich), a TFAsalt of compound 30 was prepared.

Example 31 Synthesis of Compound 31

[0497]

[0498] Using a coupling procedure similar to that described in Example1, except replacing theN′-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide with3-chloro-4-methoxyaniline (available from Aldrich), a TFA salt ofcompound 31 was prepared.

Example 32 Synthesis of Compound 32

[0499]

[0500] Using a coupling procedure similar to that described in Example1, except replacing theN′-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide with3,4,5-trimethoxyaniline (available from Aldrich), a TFA salt of compound32 was prepared. m/z: [M+H⁺] calcd for C₂₆H₃₂N₂O₆ 469.2; found 469.2.

Example 33 Synthesis of Compound 33

[0501]

[0502] Using a coupling procedure similar to that described in Example1, except replacing theN′-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide with4-benzyloxyaniline hydrochloride (available from Aldrich), a TFA salt ofcompound 33 was prepared. m/z: [M+H⁺] calcd for C₃₀H₃₂N₂O₄ 485.2; found485.2.

Example 34 Synthesis of Compound 34

[0503]

[0504] Using a coupling procedure similar to that described in Example1, except replacing theN′-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide with3,4-dimethoxyaniline (available from Aldrich), a TFA salt of compound 34was prepared. m/z: [M+H⁺] calcd for C₂₅H₃₀N₂O₅ 439.2; found 439.2.

Example 35 Synthesis of Compound 35

[0505]

[0506] Using a coupling procedure similar to that described in Example1, except replacing theN′-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide with3,4-(trimethylenedioxy)aniline (available from Maybridge), a TFA salt ofcompound 35 was prepared. m/z: [M+H⁺] calcd for C₂₆H₃₀N₂O₅ 451.2; found451.2.

Example 36 Synthesis of Compound 36

[0507]

[0508] Using a coupling procedure similar to that described in Example1, except replacing theN¹-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide with4-isopropoxyaniline (available from TCI America), a TFA salt of compound36 was prepared.m/z: [M+H⁺] calcd for C₂₆H₃₂N₂O₄ 437.2; found 437.2.

Example 37 Synthesis ofN-{2-[4-(4-ethoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine(37)

[0509]

[0510] To a mixture of 3.0 g (4.98 mmol) of compound F, prepared in partc below, in 70 ml of ethanol was added 1.0 g of 10% Palladium on carbonunder a stream of nitrogen. The flask was fitted with a balloon ofhydrogen gas, and the reaction was vigorously stirred for 1.5 hours. Thereaction was filtered through celite, using methanol to rinse, and thefiltrate was concentrated under reduced pressure. The residue wasdissolved in 40 ml of 1/1 isopropanol/methanol, 2.74 ml of 4M HCl indioxane was added, and the product was precipitated as the di-HCl saltby adding the solution to a large volume of EtOAc. The solids wereisolated by filtration to give the di-HCl salt of compound 37 as a whitesolid. ¹H NMR (300 MHz, DMSO-d6) δ 8.94 (br s, 1H), 8.63 (br s, 1H),6.97-6.67 (m, I 1H), 4.76 (m, 1H), 4.39 (s, 2H), 4.29 (br, 4H), 3.87(dd, 2H), 3.02-2.76 (m, 6H), 1.22 (t, 3H). m/z: [M+H⁺] calcd forC₂₅H₃₀N₂O₄ 423.2; found 423.2.

[0511] The intermediate compound F was prepared as follows.

[0512] a. Synthesis of Compound C.

[0513] To a flask containing 3.0 g (7.7 mmol) of compound B, 1.26 g (9.1mmol, Example 13, part b) of para-phenetidine (4-ethoxyaniline,available from Aldrich), 0.32 g (0.35 mmol) oftris(dibenzylidineacetone)dipalladium(0), 0.65 g (1.0Smmol) ofracemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, and 0.88 g (9.1mmol) of sodium tert-butoxide was added 35 ml of toluene, and themixture was heated at 95° C. for 5.5 hours under a nitrogen atmosphere.The mixture was partitioned between 1.0 M aqueous NaHSO₄ and diethylether, and the phases were separated. The diethyl ether phase wasdiluted with one volume of hexanes, and was washed once each with 1.0 Maqueous NaHSO₄ and brine, dried over Na₂SO₄, filtered, and concentratedto a dark oil. The oil was purified by chromatography, using 15%EtOAc/85% hexanes as eluent, to give 2.52 g (73%) of compound C as adark orange oil. ¹H NMR (300 MHz, DMSO-d6) δ 7.64 (s, 1H), 7.28-7.13 (m,5H), 6.91-6.72 (m, 8H), 4.27 (s, 2H), 3.92 (q, 2H), 3.25 (s, 2H), 3.15(m, 2H), 2.52 (m, 2H), 1.31 (s, 9H), 1.21 (t, 3H). m/z: [M+H⁺] calcd forC₂₈H₃₄N₂O₃ 447.3; found 447.8.

[0514] b. Synthesis of Compound E.

[0515] To 2.93 g (6.56 mmol) of compound C in 15 ml of CH₂Cl₂ at 0° C.was added 15 ml of trifluoroacetic acid. After 40 minutes, the solutionwas concentrated under reduced pressure, and the residue was partitionedbetween 1M NaOH and EtOAc. The phases were separated, and the EtOAcphase was washed once each with water and brine, dried over Na₂SO₄,filtered, and concentrated to an orange oil. The oil was dissolved in 20ml of isopropanol, 1.86 g (6.56 mmol) of the epoxide a was added, andthe solution was heated at 78° C. overnight. The mixture was cooled toroom temperature, and concentrated under reduced pressure to givecompound E as an orange oil that was used without purification in thenext step.

[0516] c. Synthesis of Compound F.

[0517] To 6.56 mmol of crude compound E from the previous step in 40 mLof tetrahydrofuran at 0° C. was added 16.4 mL (16.4 mmol) of IM lithiumaluminum hydride in tetrahydrofuran. After 2 hours, the reaction wasquenched by slow addition of sodium sulfate decahydrate. The slurry wasdiluted with diethyl ether, dried over Na₂SO₄, filtered, andconcentrated to an orange oil. The oil was purified by chromatography,using 50% EtOAc/50% hexanes as eluent, to give compound F as anoff-white foam. ¹H NMR (300 MHz, DMSO-d6) δ 7.61 (s, 1H), 7.37-6.71 (m,21H), 5.02 (s, 2H), 4.94 (m, 1H), 4.67 (m, 1H), 4.55 (m, 1H), 4.48 (d,2H), 3.85 (dd, 2H), 3.63 (dd, 2H), 2.53 (m, 6H), 1.21 (t, 3H).

[0518] The intermediate epoxide a can be prepared as described by R.Hett et al., Tetrahedron Lett., 1994, 35, 9357-9378.

Example 38 Synthesis ofN-{2-[4-(4-ethoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine(38)

[0519]

[0520] To a solution of 200 mg of compound Q (0.36 mmol) in 5.0 mLmethanol was added 45 mg of 10% palladium on carbon. The reaction wasplaced under 1 atm H₂ gas. After 20 h, an additional 25 mg of 10%palladium on carbon was added and the reaction was stirred under 1 atmH₂ for an additional 24 h after which time the reaction was filtered.The filtrate was concentrated and purified by reversed phase preparativeHPLC (gradient of 15-50% acetonitrile in 0.1% TFA). Fractions containingpure product were combined and lyophilized to afford a TFA salt ofcompound 6 as a powder. A sample of the TFA salt (39.7 mg) was dissolvedin acetonitrile (1.0 mL), diluted with water (2.0 mL) and then 0.1 N HCl(5.0 mL). The solution was frozen and lyophilized to afford thehydrochloride salt of compound 38 (38.3 mg) as a yellow powder. ¹H NMR(300 MHz, DMSO-d6) δ 10.5 (br s, 2H), 9.20 (br s, 1H), 8.75 (br s, 1H),8.22 (d, 1H) 7.15 (d, 1H), 6.95-7.05 (m, 5H), 6.80-6.90 (m, 4H), 6.56(d, 1H), 5.40 (dd, 1H), 3.95 (quar, 2H), 2.95-3.18 (m, 4H), 2.80-2.95(m, 2H), 1.29 (t, 3H); m/z: [M+H⁺] calcd for C₂₇H₂₉N₃O₄ 460.22; found460.2.

[0521] The intermediate compound Q was prepared as follows.

[0522] a. Synthesis of Compound X.

[0523] To 7.03 g (35.1 mmol) of 4-bromophenethylamine (Sigma-Aldrich) in60 mL of THF was added 8.6 g (39.4 mmol) of di-tert-butyldicarbonate.After 10 minutes, the solution was concentrated under reduced pressure,and the residue was partitioned between saturated aqueous sodiumbicarbonate and ethyl acetate. The ethyl acetate phase was washed withbrine, dried over MgSO₄, filtered, and concentrated to give compound Xas a white solid.

[0524] b. Synthesis of Compound Y.

[0525] To a flask containing 1.2 g (4.1 mmol) of compound X, 0.72 g (5.3mmol) of para-phenetidine (4-ethoxyaniline, Sigma-Aldrich), 0.19 g (0.35mmol) of tris(dibenzylidineacetone)dipalladium(0), 0.38 g (0.61 mmol) ofrac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, and 0.51 g (5.3 mmol)of sodium tert-butoxide, was added 35 mL of toluene, and the mixture washeated at 95° C. for 16 hours under an nitrogen atmosphere. The mixturewas partitioned between 1.0 M aqueous NaHSO₄ and diethyl ether. Thediethyl ether phase was washed once each with saturated NaHCO₃ andbrine, dried over MgSO₄, filtered, and concentrated to a dark oil. Theoil was purified by silica gel chromatography, using 15% EtOAc/85%hexanes as eluant, to give compound Y as a dark orange oil.

[0526] c. Synthesis of Compound Q.

[0527] To 1.0 g of compound Y (2.8 mmol) in 5 mL CH₂Cl₂ was added 4 mLTFA. After 15 minutes, the solution was concentrated, diluted with 50 mLisopropyl acetate and washed twice with 1.0 M aqueous NaOH. Theisopropyl acetate layer was dried over MgSO₄, filtered, and concentratedto a brown oil. The oil was dissolved in 5.0 mL of isopropanol and 390mg (1.3 mmol) of epoxide P (Example 15, part a) were added. The solutionwas heated to 70° C. After 36 h, the solution was concentrated and theproduct purified by reversed phase HPLC (gradient of 20-70% acetonitrilein 0.1% TFA). Fractions containing pure product were combined andconcentrated to remove acetonitrile. The aqueous residue was dilutedwith brine and extracted with ethyl acetate. The ethyl acetate layer wasdried over MgSO₄ and concentrated to afford compound Q as a yellow foam.

Example 39 Synthesis of Compound 39

[0528]

[0529] Using a coupling procedure similar to that described in Example1, except replacing theN′-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide with3,4-dimethylaniline (available from Aldrich), a TFA salt of compound 39was prepared.

Example 40 Synthesis of Compound 40

[0530]

[0531] Using a coupling procedure similar to that described in Example1, except replacing theN¹-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide with 5-aminoindan(available from Aldrich), a TFA salt of compound 40 was prepared.

Example 41 Synthesis of Compound 41

[0532]

[0533] Using a coupling procedure similar to that described in Example1, except replacing theN¹-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide with m-toluidine(available from Aldrich), a TFA salt of compound 41 was prepared.

Example 42 Synthesis of Compound 42

[0534]

[0535] Using a coupling procedure similar to that described in Example1, except replacing theN¹-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide with4-aminodiphenylamine (available from Aldrich), a TFA salt of compound 42was prepared.

Example 43 Synthesis of Compound 43

[0536]

[0537] Using a coupling procedure similar to that described in Example1, except replacing theN¹-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide with 3-ethylaniline(available from Aldrich), a TFA salt of compound 43 was prepared. m/z:[M+H⁺] calcd for C₂₅H₃₀N₂O₃ 407.2; found 407.2.

Example 44 Synthesis of Compound 44

[0538]

[0539] Using a coupling procedure similar to that described in Example1, except replacing theN¹-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide with3-methyl-4-isopropylaniline hydrochloride (available from AvocadoChemicals), a TFA salt of compound 44 was prepared. m/z: [M+H⁺] calcdfor C₂₇H₃₄N₂O₃ 435.3; found 435.2.

Example 45 Synthesis of Compound 45

[0540]

[0541] Using a coupling procedure similar to that described in Example1, except replacing theN¹-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide with4-(trifluoromethoxy)aniline (available from Aldrich), a TFA salt ofcompound 45 was prepared. m/z: [M+H⁺] calcd for C₂₄H₂₅F₃N₂O₄ 463.2;found 463.2.

Example 46 Synthesis of Compound 46

[0542]

[0543] Using a coupling procedure similar to that described in Example1, except replacing theN′-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide with4-amino-2-cyclohexylphenol (available from Sigma-Aldrich Library of RareChemicals), a TFA salt of compound 46 was prepared. m/z: [M+H⁺] calcdfor C₂₉H₃₆N₂O₄ 477.3; found 477.2.

Example 47 Synthesis of Compound 47

[0544]

[0545] Using a coupling procedure similar to that described in Example1, except replacing theN¹-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide with 2-naphthylamine(available from Aldrich), a TFA salt of compound 47 was prepared.

Example 48 Synthesis ofN-{2-[4-(3-phenylphenyl)aminophenyl]ethyl}-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine(48)

[0546]

[0547] Using a coupling procedure similar to that described in Example1, except replacing theN′-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide with 3-aminobiphenyl(available from Trans World Chemicals, Inc.), a TFA salt of compound 48was prepared.

Example 49 Synthesis ofN-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-(3-hydroxymethyl-4hydroxyphenyl)ethylamine(49)

[0548]

[0549] Using a coupling procedure similar to that described in Example1, except replacing theN¹-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide with3-phenyl-p-anisidine hydrochloride (available from Trans WorldChemicals, Inc.), a TFA salt of compound 49 was prepared.

Example 50 Synthesis of Compound 50

[0550]

[0551] Using a coupling procedure similar to that described in Example1, except replacing theN¹-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide with6-amino-3,4-benzocoumarin (available from Aldrich), a TFA salt ofcompound 50 was prepared. m/z: [M+H⁺] calcd for C₃₀H₂₈N₂O₅ 497.2; found497.1.

Example 51 Synthesis of Compound 51

[0552]

[0553] Using a coupling procedure similar to that described in Example1, except replacing theN′-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide with 4-aminobiphenyl(available from Aldrich), a TFA salt of compound 51 was prepared. m/z:[M+H⁺] calcd for C₂₉H₃₀N₂O₃ 455.2; found 455.2.

Example 52 Synthesis ofN-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine(52)

[0554]

[0555] To 2.0 g (3.10 mmol) of compound H in 50 mL of ethanol was added0.70 g of 10% palladium on carbon under a stream of nitrogen. The flaskwas fitted with a balloon of hydrogen gas, and the reaction wasvigorously stirred for 1.5 hours. The reaction was filtered throughcelite, using methanol to rinse, and the filtrate was concentrated underreduced pressure. The residue was dissolved in 20 mL isopropanol, 1.65mL of 4.0 N HCl in dioxane was added, and the product was precipitatedby adding the solution to a large volume of diethyl ether. The solidswere isolated by filtration to give 1.43 g (80%) of a hydrochloride saltof compound 52 as a white solid. ¹H NMR (300 MHz, DMSO-d6) δ 9.4 (b,1H), 9.01 (br s, 1H), 8.65 (br s, 1H), 7.39-7.22 (m, 6H), 6.99-6.83 (m,8H), 6.69 (d, 1H), 5.45 (br, 4H), 4.77 (m, 1H), 4.39 (s, 2H), 3.62 (s,3H), 3.02-2.78 (m, 6H). m/z: [M+H⁺] calcd for C₃₀H₃₂N₂O₄ 485.2; found485.4.

[0556] The intermediate compound H was prepared as follows.

[0557] a. Synthesis of Compound D.

[0558] To a flask containing 3.91 g (10 mmol) of compound B (Example 13,part b), 3.06 g (13 mmol) of 4-methoxy-3-phenylaniline hydrochloride(from TCI), 0.46 g (0.5 mmol) oftris(dibenzylidineacetone)dipalladium(0), 0.93 g (1.5 mmol) ofracemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, and 2.21 g (23mmol) of sodium tert-butoxide was added 50 mL of toluene, and themixture was heated at 95° C. for 5.5 hours under an nitrogen atmosphere.The mixture was partitioned between 1.0 M aqueous NaHSO₄ and diethylether, and the phases were separated. The diethyl ether phase wasdiluted with one volume of hexanes, and was washed once each with 1.0 Maqueous NaHSO₄ and brine, dried over Na₂SO₄, filtered, and concentratedto a dark oil. The oil was purified by silica gel chromatography, using12% EtOAc/88% hexanes as eluent, to give compound D as a yellow foam. ¹HNMR (300 MHz, DMSO-d6) δ 7.76 (s, 1H), 7.38-7.13 (m, 10H), 6.95-6.81 (m,7H), 4.28 (s, 2H), 3.61 (s, 3H), 3.16 (m, 2H), 2.53 (m, 2H), 1.29 (s,9H).

[0559] b. Synthesis of Compound G.

[0560] To 2.60 g (5.11 mmol) of compound D in 15 mL of CH₂Cl₂ at 0° C.was added 15 mL of trifluoroacetic acid. After 40 minutes, the solutionwas concentrated under reduced pressure, and the residue was partitionedbetween 1M aqueous NaOH and EtOAc. The phases were separated, and theEtOAc phase was washed once each with water and brine, dried overNa₂SO₄, filtered, and concentrated to an orange residue. The residue wasdissolved in 15 mL of isopropanol, 1.45 g (5.11 mmol) of the epoxide a(Example 37, part b) was added, and the solution was heated at 78° C.overnight. The mixture was cooled to room temperature, and concentratedunder reduced pressure to give compound G as an orange oil which wasused in the next step without purification.

[0561] c. Synthesis of Compound H.

[0562] To 5.11 mmol of crude compound G from the previous step in 40 mLof tetrahydrofuran at 0° C. was added 12.7 mL (12.7 mmol) of 1.0 Mlithium aluminum hydride in tetrahydrofuran. After 2 hours, the reactionwas quenched by slow addition of sodium sulfate decahydrate. The slurrywas diluted with diethyl ether, dried over Na₂SO₄, filtered, andconcentrated to an orange oil. The oil was purified by chromatography,using 50% EtOAc/50% hexanes as eluent, to give 2.0 g (61%, 2 steps) ofcompound H as a white foam. ¹H NMR (300 MHz, DMSO-d6) δ 7.72 (s, 1H),7.38-6.77 (m, 25H), 5.00 (s, 2H), 4.92 (m, 1H), 4.65 (m, 1H), 4.55 (m,1H), 4.45 (d, 2H), 3.62 (s, 2H), 3.61 (s, 3H), 2.52 (m, 6H).

Example 53 Synthesis ofN-{2-[4-(3-phenyl-4-ethoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine(53)

[0563]

[0564] To a mixture of 825 mg (1.22 mmol) of compound N in 15 mL ofethanol was added 260 mg of 10% palladium on carbon under a stream ofnitrogen. The flask was fitted with a balloon of hydrogen gas, and thereaction was vigorously stirred for 3 hours. The reaction was filteredthrough celite, using methanol to rinse, and the filtrate wasconcentrated under reduced pressure. The residue was dissolved in 10 mLisopropanol, 0.67 mL of 4.0 M HCl in dioxane was added, and the productwas precipitated by adding the solution to a large volume of EtOAc. Thesolids were isolated by filtration to give a hydrochloride salt ofcompound 53 as a white solid. m/z: [M+H⁺] calcd for C₃₁H₃₂N₂O₄ 499.3;found 499.3.

[0565] The intermediate compound N was prepared as follows.

[0566] a. Synthesis of Compound J.

[0567] 4.84 g (20.5 mmol) of 4-methoxy-3-phenylaniline hydrochloride(available from TCI) was partitioned between diethyl ether and 1.0 Maqueous NaOH, and the phases were separated. The diethyl ether phase waswashed once each with water and brine, dried over K₂CO₃, filtered, andconcentrated to a brown solid. The solid was dissolved in 100 mL ofCH₂Cl₂, the solution was cooled to 0° C., and 21.2 g (84.6 mmol) ofboron tribromide was added. After 20 minutes, the reaction was pouredover 500 mL of ice, and the mixture was stirred overnight. The mixturewas washed twice with EtOAc to remove oxidized material, and the EtOAcphases were discarded. The acidic phase was basified with solid NaHCO₃,and was extracted twice with EtOAc. The combined EtOAc phases werewashed once with brine, dried over Na₂SO₄, filtered, and concentrated togive 2.48 g of compound J as a brown solid. ¹H NMR (300 MHz, DMSO-d6) δ8.37 (s, 1H), 7.41-7.14 (m, 5H), 6.57-6.32 (m, 3H), 4.45 (s, 2H).

[0568] b. Synthesis of Compound K.

[0569] To 2.28 g (12.2 mmol) of compound J in 45 mL of dimethylformamideat 0° C. was added 734 mg (18.4 mmol) of 60% NaH in oil. After 10minutes, 1.90 g (12.2 mmol) of iodoethane was added. After 20 minutes,the solution was partitioned between diethyl ether and 5% aqueousNa₂SO₃, and the phases were separated. The diethyl ether phase waswashed once each with 1.0 M aqueous NaOH, water, and brine, dried overNa₂SO₄, and concentrated to give compound K as a dark brown oil. ¹H NMR(300 MHz, DMSO-d6) δ 7.37-7.19 (m, 5H), 6.73 (d, 1H), 6.47-6.42 (m, 2H),4.65 (s, 2H), 3.73 (q, 2H), 1.07 (t, 3H).

[0570] c. Synthesis of Compound L.

[0571] To a flask containing 3.97 g (10.7 mmol) of compound B (Example13, part b), 2.27 g (12.2 mmol) of compound K, 0.46 g (0.5 mmol) oftris(dibenzylidineacetone)dipalladium (0), 0.95 g (1.5 mmol) ofracemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, and 1.27 g (13.3mmol) of sodium tert-butoxide was added 48 nL of toluene, and themixture was heated at 95° C. for 5.5 hours under an nitrogen atmosphere.The mixture was partitioned between 1.0 M aqueous NaHSO₄ and diethylether, and the phases were separated. The diethyl ether phase wasdiluted with one volume of hexanes, and was washed once each with 1.0 Maqueous NaHSO₄ and brine, dried over Na₂SO₄, filtered, and concentratedto a dark oil. The oil was purified by silica gel chromatography, using10% EtOAc/90% hexanes as eluent, to give 4.13 g (77%) of compound L as ayellow foam. ¹H NMR (300 MHz, DMSO-d6) δ 7.76 (s, 1H), 7.42-7.13 (m,10H), 6.93-6.81 (m, 7H), 4.27 (s, 2H), 3.86 (q, 2H), 3.25 (m, 2H), 2.53(m, 2H), 1.28 (s, 9H), 1.13 (t, 3H).

[0572] d. Synthesis of Compound M.

[0573] To 1.40 g (2.68 mmol) of compound L in 15 mL of CH₂Cl₂ at 0° C.was added 15 mL of trifluoroacetic acid. After 40 minutes, the solutionwas concentrated under reduced pressure, and the residue was partitionedbetween 1.0 M aqueous NaOH and EtOAc. The phases were separated, and theEtOAc phase was washed once each with water and brine, dried overNa₂SO₄, filtered, and concentrated to an orange residue. The residue wasdissolved in 15 ntL of isopropanol, 1.45 g (2.68 mmol) of the epoxide a(Example 37, part b) was added, and the solution was heated at 78° C.overnight. The mixture was cooled to room temperature, and concentratedunder reduced pressure to give an orange oil that was taken on withoutanalysis.

[0574] e. Synthesis of Compound N.

[0575] To 2.68 mmol of crude compound M in 20 mL of tetrahydrofuran at0° C. was added 7.0 mL (7.0 mmol) of 1.0 M lithium aluminum hydride intetrahydrofuran. After 2 hours, the reaction was quenched by slowaddition of sodium sulfate decahydrate. The slurry was diluted withdiethyl ether, dried over Na₂SO₄, filtered, and concentrated to anorange oil. The oil was purified by silica gel chromatography, using 50%EtOAc/50% hexanes as eluent, to give 835 mg of compound N as a whitefoam. ¹H NMR (300 MHz, DMSO-d6) δ 7.73 (s, 1H), 7.42-6.77 (m, 25H), 5.00(s, 2H), 4.93 (m, 1H), 4.66 (d, 1H), 4.51 (m, 1H), 4.47 (m, 2H), 3.86(q, 2H), 3.62 (m, 2H), 2.55 (m, 6H), 1.13 (t, 3H).

Example 54 Synthesis ofN-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine(54)

[0576]

[0577] To a mixture of 1.24 g (1.83 mmol) of compound I in 30 mL ofethanol and 20 mL of methanol was added 400 mg of 10% palladium oncarbon under a stream of nitrogen. The flask was fitted with a balloonof hydrogen gas, and the reaction was vigorously stirred for 1.5 hours.The reaction was filtered through celite, using methanol to rinse, andthe filtrate was concentrated under reduced pressure. The residue wasdissolved in 20 mL isopropanol, 0.21 mL of 4.0 M HCl in dioxane wasadded, and the product was precipitated by adding the solution to alarge volume of EtOAc. The solids were isolated by filtration to give447 mg of a hydrochloride salt of compound 54 as a white solid. ¹H NMR(300 MHz, DMSO-d6) δ 10.03 (br s, 1H), 9.55 (s, 1H), 8.81 (br s, 1H),8.59 (br s, 1H), 8.20 (d, 1H), 8.07 (d, 1H), 7.39-7.20 (m, 5H),6.99-6.79 (m, 10H), 4.75 (m, 1H), 3.62 (s, 3H), 3.03-2.72 (m, 6H). m/z:[M+H⁺] calcd for C₃₀H₃₁N₃O₄ 498.2; found 498.5.

[0578] The intermediate compound I was prepared as follows.

[0579] a. Synthesis of Compound I.

[0580] To 944 mg (1.85 mmol) of compound D (Example 52, part a) in 6 mLof CH₂Cl₂ at 0° C. was added 6 mL of trifluoroacetic acid. After 40minutes, the solution was concentrated under reduced pressure, and theresidue was partitioned between 1.0 M aqueous NaOH and EtOAc. The phaseswere separated, and the EtOAc phase was washed once each with water andbrine, dried over Na₂SO₄, filtered, and concentrated to an orange oil.

[0581] The residue from above was dissolved in 5 mL of isopropanol, 500mg (1.85 mmol) of the epoxide b was added, and the solution was heatedat 78° C. overnight. The mixture was cooled to room temperature, andconcentrated under reduced pressure to give an orange oil. The oil waspurified by silica gel chromatography, using 50 EtOAc/50 hexanes aseluent, to give 825 mg (66%) of compound I as a white foam. ¹H NMR (300MHz, DMSO-d6) δ 9.45 (s, 1H), 8.24 (d, 1H), 8.09 (d, 1H), 7.72 (s, 1H),7.42-6.77 (m, 25H), 5.09 (s, 2H), 4.49 (m, 1H), 3.67 (m, 2H), 3.61 (s,3H), 2.50 (m, 6H).

[0582] The intermediate epoxide b can be prepared as described in U.S.Pat. No. 6,268,533 B1, and in R. Hett. et al., Organic Process Researchand Development, 1998, 2, 96-99.

Example 55 Synthesis ofN-{2-[4-(3-phenyl-4-ethoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine(55)

[0583]

[0584] To a mixture of 746 mg (1.07 mmol) of compound 0 in 15 mL ofethanol and 5 mL of EtOAc was added 260 mg of 10% palladium on carbonunder a stream of nitrogen. The flask was fitted with a balloon ofhydrogen gas, and the reaction was vigorously stirred for 3 hours. Thereaction was filtered through celite, using methanol to rinse, and thefiltrate was concentrated under reduced pressure. The residue wasdissolved in 20 mL isopropanol, 0.58 mL of 4.0 M HCl in dioxane wasadded, and the product was precipitated by adding the solution to alarge volume of EtOAc. The solids were isolated by filtration to give ahydrochloride salt of compound 55 as an off white solid. ¹H NMR (300MHz, DMSO-d6) δ 10.12 (br s, 1H), 9.62 (s, 1H), 8.90 (br s, 1H), 8.67(br s, 1H), 8.27 (d, 1H), 8.14 (d, 1H), 7.25 (m, 5H) 6.85-7.08 (m, 9H),4.80 (dd, 1H), 3.94 (quar, 2H), 2.75-3.15 (m, 6H), 1.21 (t, 3H); m/z:[M+H⁺] calcd for C₃₁H₃₃N₃O₄ 512.25; found 512.5.

[0585] The intermediate compound 0 was prepared as follows.

[0586] a. Synthesis of Compound O.

[0587] To 1.4 g (2.68 mmol) of compound L (Example 53, part c) in 6 mLof CH₂Cl₂ at 0° C. was added 6 mL of trifluoroacetic acid. After 40minutes, the solution was concentrated under reduced pressure, and theresidue was partitioned between 1.0 M aqueous NaOH and EtOAc. The phaseswere separated, and the EtOAc phase was washed once each with water andbrine, dried over Na₂SO₄, filtered, and concentrated to an orangeresidue. The residue was dissolved in 5 mL of isopropanol, 721 mg (2.68mmol) of epoxide b (Example 54, part a) was added, and the solution washeated at 78° C. overnight. The mixture was cooled to room temperature,and concentrated under reduced pressure to give an orange oil. The oilwas purified by silica gel chromatography using 50 EtOAc/50 hexanes aseluent, to give 756 mg of compound 0 as a white foam. ¹H NMR (300 MHz,DMSO-d6) δ 9.45 (d, 1H), 8.25 (d, 1H), 8.14 (d, 1H), 7.72 (s, 1H),7.45-6.76 (m, 25H), 5.10 (s, 2H), 5.04 (m, 1H), 3.94 (q, 2H), 3.61 (s,2H), 2.50 (s, 6H), 1.13 (t, 3H).

Example 56 Synthesis ofN-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine(56)

[0588]

[0589] To a solution of 840 mg of compound S (1.2 mmol) in 40 mL of 1:1methanol:THF was added 170 mg of 10% palladium on carbon. The reactionwas shaken under an atmosphere of 35 psi H₂. After 24 h, the reactionwas filtered and the filtrate purified by reversed-phase HPLC (gradientof 10 to 70% acetonitrile in 0.1% aqueous TFA). Fractions containingpure product were combined and lyophilized to afford a TFA salt ofcompound 56 as a powder.

[0590] A sample of the TFA salt (75 mg) was dissolved in acetonitrile(1.0 mL) and diluted with water (2.0 mL) followed by 0.1 N HCl (3.0 mL).The solution became cloudy. Addition of 1.5 mL acetonitrile afforded aclear solution which was frozen and lyophilized. The residue wasredissolved in acetonitrile (1.0 mL) and diluted with water (2.0 mL)followed by 0.1 N HCl (4.0 mL). The solution became cloudy. Addition of1.0 mL acetonitrile afforded a clear solution which was frozen andlyophilized. The hydrochloride salt of compound 56 (50 mg) was obtainedas a gray solid. ¹H NMR (300 MHz, DMSO-d6) δ 10.55 (br s, 1H), 9.30 (brs, 1H), 8.80, (br s, 1H), 8.24 (d, 1H), 7.25-7.48 (m, 5H), 6.92-7.18 (m9H), 6.55 (d, 1H), 5.55 (d, 1H), 3.69 (s, 3H) 2.80-3.20 (m, 6H) m/z:[M+H⁺] calcd for C₃₂H₃₁N₃O₄ 522.24; found 522.3.

[0591] The intermediate compound S was prepared as follows.

[0592] a. Synthesis of Compound S.

[0593] A solution of compound D (800 mg, 1.6 mmol, Example 52, part a)in 5 mL CH₂Cl₂ was cooled to 0° C. and 5 mL of TFA was added. After 20min, the reaction was concentrated and the residue dissolved in ethylacetate. The ethyl acetate solution was washed twice with 1.0 M aqueousNaOH followed by water and then dried over MgSO₄, filtered andconcentrated to an oil. The oil was dissolved in 3 mL DMF andbromoketone R (800 mg, 2.1 mmol) and K₂CO₃ (650 mg, 4.7 mmol) wereadded. The reaction was heated to 40° C. After 1 h, the reaction wascooled and diluted with 5 mL methanol. NaBH₄ (150 mg, 4.0 mmol) wasadded and the reaction was stirred vigorously for 10 min. The reactionwas quenched by dripping the suspension into 100 mL of rapidly stirredsaturated aqueous NH₄Cl. Compound S precipitated and was isolated byfiltration, washed with water and dried.

[0594] The intermediate bromoketone R can be prepared as described inExample 611B, parts a-d. See also EP 0 147 791 B.

Example 57 Synthesis of Compound 57

[0595]

[0596] Using a coupling procedure similar to that described in Example1, except replacing theN¹-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanilamide withmethyl-4-aminobenzoate (available from Aldrich), a TFA salt of compound57 was prepared. m/z: [M+H⁺] calcd for C₂₅H₂₈N₂O₅ 437.2; found 437.2.

Example 58 Synthesis of Compound 58

[0597]

[0598] Using a coupling procedure similar to that described in Example1, except replacing theN¹-(4-heptyl-6-methyl-2-pyrimidinyl)sulfanisamide with2-(4-aminophenyl)-3-methyl-3-pyrazolin-5-one (available fromSigma-Aldrich Library of Rare Chemicals), a TFA salt of compound 58 wasprepared. m/z: [M+H⁺] calcd for C₂₇H₃₀N₄O₄ 475.2; found 475.2.

Example 59 Synthesis of Compound 59

[0599]

[0600] To a mixture of compound jj (0.2 g, 0.27 mmol) in 6 mL DMF/EtOH(1:1) was added 50 mg of 10% palladium on carbon. The reaction wasagitated under H₂ at 40 psi for 8 hours. The slurry was filtered andpurified by reversed phase HPLC (gradient of 10 to 50% acetonitrile in0.1% aqueous TFA). Fractions containing pure product were combined andlyophilized to afford compound 59 as a TFA salt. The TFA salt productwas solubilized in acetonitrile/water (1:1, 2 mL) to which 1.5 fnL of0.1 N aqueous HCl was added. The solution was frozen and lyophilized toafford compound 59 as an HCl salt. m/z: [M+H⁺] calcd for C₃₀H₂₉N₅O₅S572.7; found 572.3.

[0601] The intermediate jj was prepared as follows.

[0602] a. Synthesis of Compound jj

[0603] To compound HH (4.5 g, 8.1 mmol) (Example 14, part a), in 20 mlCH₂Cl₂ was added 1.5 mL TFA. After 1 hour, the solution wasconcentrated, basified with 1.0 N aqueous sodium hydroxide and extractedtwice with CH₂Cl₂, followed by an extraction using ethyl acetate. Theorganic layers were combined, dried over MgSO₄, filtered andconcentrated to an oil. The oil was purified by silica gelchromatography (gradient of 2 to 10% methanol in methylene chloride). Tothe purified product (0.42 g, 0.92 mmol) was added epoxide P (Example15, part a) (022 g, 0.76 mmol) and isopropanol (410 mL). The slurry wasstirred at 70° C. Methylene chloride was added until a homogenoussolution was obtained. After 40 h, the reaction was cooled to roomtemperature and the solvents were evaporated under reduced pressure. Theresidue was purified by silica gel chromatography (2% methanol inmethylene chloride) to afford compound jj.

Example 60 Synthesis of Compound 60

[0604]

[0605] To a mixture of compound pp (0.3 g, 0.45 mmol) in 10 mL anhydrousEtOH was added 100 mg of 10% palladium on carbon. The reaction wasagitated under H₂ at 40 psi for 18 h. The reaction was filtered andpurified by reversed phase HPLC (gradient of 10 to 50% acetonitrile in0.1% aqueous TFA). Fractions containing pure product were combined andlyophilized to afford compound 60 as a TFA salt. The TFA salt productwas solubilized in acetonitrile/water (1:2, 100 mL) to which 6 mL of 0.1N aqueous HCl was added. The solution was frozen and lyophilized toafford compound 60 as an HCl salt. m/z: [M+H⁺] calcd for C₂₇H₂₉N₅O₄488.6; found 488.3.

[0606] The intermediate compound pp was prepared as follows.

[0607] a. Synthesis of Compound cc

[0608] To a flask containing compound B (Example 13, part b) (3.75 g,9.6 mmol), 2-(4-aminophenyl)-3-methyl-3-pyrazolin⁻⁵-one (2.0 g, 10.6mmol) (available from Sigma-Aldrich Library of Rare Chemicals),tris(dibenzylidineacetone)dipalladium(0) (0.44 g, 0.48 mmol),racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.90 g, 1.44 mmol),and sodium tert-butoxide (2.20 g, 12.5 mmol) was added toluene (50 mL).The mixture was stirred at 95° C. for 6 h under a nitrogen atmosphere.The mixture was diluted with 200 mL diethyl ether and washed twice with100 mL portions of 1.0 M aqueous NaHSO₄, followed by 100 mL of saturatedaqueous NaHCO₃. The diethyl ether phase was dried over MgSO₄, filtered,and concentrated to a dark oil. The oil was purified by silica gelchromatography (gradient of 30 to 40% ethyl acetate in hexanes) toafford compound cc as an orange foam.

[0609] h. Synthesis of Compound pp.

[0610] To compound cc (0.99 g, 1.99 mmol) in 5 mL CH₂Cl₂ was added 2 mLTFA. After 1 h, the solution was concentrated, diluted with 15 mL CH₂Cl₂and washed with 1.0 N aqueous sodium hydroxide. The aqueous wascollected and washed again with CH₂Cl₂ (10 mL) followed by a wash withethyl acetate (10 mL). The organic layers were combined and dried overMgSO₄, filtered, and concentrated under reduced pressure. The crudeproduct was purified by silica gel chromatography (gradient of 2-10%MeOH in CH₂Cl₂) to afford an oil (2.1 g). A portion of this product (0.5g, 1.26 mmol) was solubilized in 10 mL of 1:1 methanol:THF. BromohydrinGG (Example 13, part d) (0.42 g, 1.20 mmol) and K₂CO₃ (0.44 g, 3.15mmol) were added and the slurry was stirred at room temperature for 1.5h. The reaction was concentrated and the residue was diluted with 30 mLwater and extracted twice with 30 mL portions of toluene. The tolueneextracts were combined, dried over Na₂SO₄, filtered, and concentrated.The residue was heated to 120° C. After 2 h, the reaction was cooled toroom temperature and the crude compound was purified by silica gelchromatography (gradient of 5-10% MeOH in CH₂Cl₂) to afford compound ppas a tan colored solid (0.7 g).

Example 61A Synthesis ofN-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine(61)

[0611]

[0612] To a solution of 200 mg of compound T (0.28 mmol) in 4 mL ofacetic acid was added 100 mg of 10% palladium on carbon. The reactionwas shaken under an atmosphere of 40 psi H₂. After 17 h, the reactionwas filtered and the filtrate purified by reversed-phase HPLC (gradientof 10 to 70% acetonitrile in 0.1% aqueous TFA). Fractions containingpure product were combined and lyophilized to afford compound 61 as apowder.

[0613] The intermediate compound T was prepared as follows:

[0614] a. Synthesis of Compound T

[0615] To 1.13 g of compound D (2.2 mmol, Example 52, part a) in 4 mLCH₂Cl₂ was added 4 mL TFA. After 30 minutes, the solution wasconcentrated and diluted with 20 mL ethyl acetate and 20 mL water. ThepH was raised to 11 by addition of 6.0 N aqueous sodium hydroxide andthe layers were separated. The ethyl acetate layer was washed once with1.0 N aqueous sodium hydroxide, dried over MgSO₄, filtered, andconcentrated to a brown oil. The oil was dissolved in 7.0 mL ofisopropanol and 600 mg (2.0 mmol) of epoxide P (Example 15, part a) wereadded. The solution was heated to 70° C. After 34 h, the solution wasconcentrated and the product partially purified by silica gelchromatography (gradient of 1 to 2% methanol in CH₂Cl₂). Fractionscontaining product were combined and concentrated to afford T as ayellow oil.

Example 61B Synthesis ofN-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine(61)

[0616] To a solution ofN-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-benzyloxy-2(1H)-quinolinon-5-yl)ethylamine(PP) (4.0 g, 6.5 mmol) in tetrahydrofuran (100 mL) and water (16 mL) wasadded 10% palladium on carbon (800 mg). The reaction was stirredvigorously under one atmosphere of hydrogen for 6.5 h. The solids werefiltered off and washed with tetrahydrofuran (4×25 mL) and then 50%methanol/tetrahydrofuran (2×25 mL). The combined filtrates wereevaporated to dryness and the crude product was purified byreverse-phase HPLC. Fractions containing pure product were combined andlyophilized. The product from several runs was combined to give 4.68 gwhich was dissolved in acetonitrile (200 mL) and water (200 mL). 1.0 NHCl (18.7 mL) was added, and the solution was lyophilized. The residuewas again dissolved in acetonitrile (125 mL) and water (125 mL). 1.0 NHCl was added and the solution was lyophilized to give a hydrochloridesalt of compound 61 as an off white powder. ¹H NMR (300 MHz, DMSO-d6) δ10.55 (br s, 1H), 9.40 (br s, 1H), 8.80, (br s, 1H), 8.26 (d, 1H), 7.60,(br s, 2H) 7.25-7.45 (m, 5H), 6.92-7.16 (m 10H), 6.55 (d, 1H), 5.45 (d,1H), 3.69 (s, 3H) 2.80-3.15 (m, 6H); m/z: [M+H⁺] calcd for C₃₂H₃₁N₃O₄522.24; found 522.4.

[0617] The intermediate PP was prepared as follows:

[0618] a. Synthesis of 8-acetoxy-2(1H)-quinolinone (CC)

[0619] 8-Hydroxyquinoline-N-oxide (160.0 g, 1.0 mol) and aceticanhydride (800 mL, 8.4 mol) were heated at 100° C. for 3 hours and thencooled in ice. The product was collected on a Buchner funnel, washedwith acetic anhydride (2×100 mL) and dried under reduced pressure togive 8-acetoxy-2(1H)-quinolinone (CC) (144 g) as a tan solid.

[0620] b. Synthesis of 5-acetyl-8-hydroxy-2(1 h)-quinolinone (DD)

[0621] A slurry of aluminum chloride (85.7 g, 640 mmol) in1,2-dichloroethane (280 mL) was cooled in ice, and compound CC (56.8 g,280 mmol) was added. The mixture was warmed to room temperature, andthen heated at 85° C. After 30 minutes acetyl chloride (1.5 nL, 21 mmol)was added and the mixture was heated an additional 60 minutes. Thereaction mixture was then cooled and added to 1N HCl (3 L) at 0° C. withstirring. After stirring for 2 hours, the solids were collected on aBuchner funnel, washed with water (3×250 mL) and dried under reducedpressure. The crude product isolated from several batches (135 g) wascombined and triturated with dichloromethane (4 L) for 6 hours. Theproduct was collected on a Buchner funnel and dried under reducedpressure to give 5-acetyl-8-hydroxy-2(1H)-quinolinone (DD) (121 g).

[0622] c. Synthesis of 5-acetyl-8-benzyloxy-2(1H)-quinolinone (EE)

[0623] To 5-acetyl-8-hydroxy-2-quinolone (37.7 g, 186 mmol) was addeddimethylformamide (200 mL) and potassium carbonate (34.5 g, 250 mmol)followed by benzyl bromide (31.8 g, 186 mmol). The mixture was stirredat room temperature for 2.25 hour and then poured into saturated sodiumchloride (3.5 L) at 0° C. and stirred well for 1 hour. The product wascollected and dried on a Buchner funnel for 1 hour, and the resultingsolids were dissolved in dichloromethane (2 L) and dried over sodiumsulfate. The solution was filtered through a pad of Celite and washedwith dichloromethane (5×200 mL). The combined filtrate was thenconcentrated to dryness and the resulting solids were triturated withether (500 mL) for 2 hours. The product was collected on a Buchnerfunnel, washed with ether (2×250 mL) and dried under reduced pressure togive 5-acetyl-8-benzyloxy-2(1H)-quinolinone (EE) (44 g) as an off whitepowder.

[0624] d. Synthesis of5-(2-bromo-1-oxy)ethyl-8-benzyloxy-2(1H)-quinolinone (R)

[0625] 5-Acetyl-8-benzyloxy-2(1H)-quinolinone (EE) (20.0 g, 68.2 mmol)was dissolved in dichloromethane (200 mL) and cooled to 0° C. Borontrifluoride diethyl etherate (10.4 mL, 82.0 mmol) was added via syringeand the mixture was warmed to room temperature to give a thicksuspension. The suspension was heated at 45° C. (oil bath) and asolution of bromine (11.5 g, 72.0 mmol) in dichloromethane (100 mL) wasadded over 40 minutes. The mixture was kept 45° C. for an additional 15minutes and then cooled to room temperature. The mixture wasconcentrated under reduced pressure and then triturated with 10% aqueoussodium carbonate (200 mL) for 1 hour. The solids were collected on aBuchner funnel, washed with water (4×100 mL) and dried under reducedpressure. The product of two runs was combined for purification. Thecrude product (52 g) was triturated with 50% methanol in chloroform (500mL) for 1 hour. The product was collected on a Buchner funnel and washedwith 50% methanol in chloroform (2×50 mL) and methanol (2×50 mL). Thesolid was dried under reduced pressure to give5-(2-bromo-1-oxy)ethyl-8-benzyloxy-2(1H)-quinolinone (R) (34.1 g) as anoff white powder.

[0626] e. Synthesis of5-(2-bromo-(R)-1-hydroxy)ethyl-8-benzyloxy-2(1H)-quinolinone (FF)

[0627] Using a procedure described in Mathre et al., J. Org. Chem.,1991, 56, 751-762, a catalyst was prepared as follows.(R)-(+)-α,α-Diphenylprolinol (10.0 g, 39 mmol) and trimethylboroxine(3.7 mL, 26 mmol) were combined in toluene (200 mL) and stirred at roomtemperature for 30 min. The mixture was placed in a 150° C. oil bath and150 mL liquid was distilled away. Toluene (50 mtL) was added, andanother 50 mL of distillate was collected. Another portion of toluene(50 mL) was added and a further 50 mL of distillate was collected. A1.00 mL aliquot of the material remaining in the pot was evaporated todryness and weighed (241.5 mg) to determine that the concentration ofcatalyst was 0.87 M.

[0628] 5-(2-Bromo-1-oxy)ethyl-8-benzyloxy-2(1H)-quinolinone (R) (30.0 g,81 mmol) was suspended in, tetrahydrofuran (1.2 L) under a nitrogenatmosphere and the catalyst from above (13 mL, 11 mmol) was added. Thesuspension was cooled to −5° C. in an ice/isopropanol bath and borane(1.0 M in THF, 97 mL, 97 mmol) was added over 3 h. The reaction wasstirred an additional 45 min at −5° C., then methanol (200 mL) was addedslowly. The mixture was concentrated under vacuum to give5-(2-bromo-(R)-1-hydroxy)ethyl-8-benzyloxy-2(1H)-quinolinone (FF).

[0629] f. Synthesis of5-(2-bromo-(R)-1-tert-butyldimethylsiloxy)ethyl-8-benzyloxy-2(1H)-quinolinone(HH)

[0630] Compound FF (15 g, 40 mmol) and 2,6-lutidine (9.3 mL, 80 mmol)were suspended in dichloromethane at 0° C. tert-Butyldimethylsilyltrifluoromethanesulfonate (18.5 mL, 80 mmol) was added dropwise. Themixture was allowed to warm to room temperature and stirred overnight.The reaction was diluted with dichloromethane (200 mL) and washed twicewith 1N hydrochloric acid, then three times with brine. The organicswere dried over magnesium sulfate and the volume was reduced to 100 mLunder vacuum. The organics were applied to a silica gel columnequilibrated with 30% ethyl acetate in hexanes and the product waseluted with 50% ethyl acetate in hexanes. Removal of the solvent underreduced pressure gave5-(2-bromo-(R)-1-tert-butyldimethylsiloxy)ethyl-8-benzyloxy-2(1H)-quinolinone(HH). (10.3 g). Unreacted starting material (compound FF, 2 g) was alsorecovered.

[0631] g. Synthesis ofN-tert-butoxycarbonyl-2-[4-(3-[phenyl-4-methoxyphenyl)aminophenyl]ethylamine(LL)

[0632] Under nitrogen, compound X (from Example 38 part a) (5.0 g, 16.7mmol) was mixed with toluene (80 mL) and 4-methoxy-3-phenylanilinehydrochloride (4.3 g, 18.3 mmol) was added to form a slurry.2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (1.6 g, 2.5 mmol) was added,followed by tris(dibenzylideneacetone)dipalladium(0) (760 mg, 0.83 mmol)and finally sodium tert-butoxide (5.3 g, 55 mmol). The mixture washeated at 90° C. for 150 min and then cooled to room temperature. Water(150 mL) was added followed by ethyl acetate (150 mL) and the phasespartitioned. The aqueous layer was extracted with ethyl acetate (150 mL)and the combined organics washed three times with 0.5 M sodium bisulfate(200 mL), once with saturated sodium bicarbonate (150 mL) and twice withsaturated sodium chloride (150 mL). The organics were dried overmagnesium sulfate (50 g) and the volatiles removed under vacuum to giveN-tert-butoxycarbonyl-2-[4-(3-[phenyl-4-methoxyphenyl)aminophenyl]ethylamine(LL) (8.4 g) which was used without further purification.

[0633] h. Synthesis of2-[4-(3-[phenyl-4-methoxyphenyl)aminophenyl]ethylamine (MM)

[0634] Under nitrogen, compound LL (94.6 g) was treated withdichloromethane (500 mL) and cooled in an ice bath. Hydrogen chloride (4M in dioxane, 125 mL, 500 mmol) was added in 10 portions over 20 min.The reaction was kept at room temperature for 130 minutes, during whichtime the product precipitated. The solid was filtered and washed withdichloromethane (350 mL) and dried under vacuum in the dark to give thedihydrochloride salt of2-[4-(3-[phenyl-4-methoxyphenyl)aminophenyl]ethylamine (MM) (37.1 g). ¹HNMR (300 MHz, DMSO-d6) δ 8.29 (br s, 2H), 8.04 (br s, 1H) 7.25-7.50 (m,5H), 6.90-7.08 (m, 7H) 3.69 (s, 3H), 2.93 (m, 2H), 2.75 (m, 2H); m/z:[M+H⁺] calcd for C₂₁H₂₂N₂O 319.18; found 319.3.

[0635] i. Synthesis ofN-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-tert-butyldimethylsiloxy-2-(8-benzyloxy-2(1H)-quinolinon-5-yl)ethylamine(NN)

[0636] The dihydrochloride salt of compound MM was partitioned betweenisopropyl acetate and 1.0 N sodium hydroxide. The organic layer wasdried over sodium sulfate and concentrated to give the free base as adark oil.

[0637] Sodium iodide (4.2 g, 28 mmol), compound HH (9.1 g, 18.6 mmol)and sodium bicarbonate (4.7 g, 55.9 mmol) were weighed into a flask.Under nitrogen, compound MM (7 g, 22 mmol) in dimethyl sulfoxide (20 mL)was added and the mixture stirred at 140° C. (oil bath) for 30 min, thencooled to room temperature. Ethyl acetate was added (200 mL) and themixture washed three times with 1N hydrochloric acid, then with 1Nsodium hydroxide, saturated sodium bicarbonate and finally saturatedsodium chloride (200 mL each). The organics were dried over sodiumsulfate and evaporated to dryness to giveN-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-tert-butyldimethylsilyl-2-(8-benzyloxy-2(1H)-quinolinon-5-yl)ethylamine(NN) (13.9 g) which was used in the next step without furtherpurification.

[0638] j. Synthesis ofN-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-benzyloxy-2(1H)-quinolinon-5-yl)ethylamine(PP)

[0639] Compound NN (13.9 g) was combined with methanol (200 mL) andconcentrated hydrochloric acid (170 mL) was added in portions(exothermic). The solution turned orange and cloudy after the additionand more methanol (100 mL) was added until a clear solution wasobtained. The mixture was stirred at room temperature overnight, inwhich time a brown gum had formed. The solvent was removed under vacuum,and ethyl acetate (300 mL) was added. The resulting mixture was cooledin an ice bath, and neutralized (pH 7) with 10 N sodium hydroxide. ThepH was then raised to 10 with 1 M sodium hydroxide to give a clearbiphasic mixture. The phases were separated and the aqueous layer wasextracted with ethyl acetate (300 mL). The combined organic layers weredried over sodium sulfate, and evaporated to dryness. The crude productwas purified by flash chromatography on silica gel (500 g, 0-10%methanol in dichloromethane) to giveN-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-benzyloxy-2(1H)-quinolinon-5-yl)ethylamine(PP) (5.6 g).

Example 61C Synthesis ofN-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine(61)

[0640] a. Synthesis of5-(2-bromo-(R)-1-hydroxy)ethyl-8-benzyloxy-2(1H)-quinolinone (FF)

[0641] (R)-(+)-α,α-Diphenylprolinol (30.0 g, 117 mmol) andtrimethylboroxine (11.1 mL, 78 mmol) were combined in toluene (300 mL)and stirred at room temperature for 30 minutes. The mixture was placedin a 150° C. oil bath and liquid was distilled off. Toluene was added in20 mL aliquots, and distillation was continued for 4 hours. A total of300 mL toluene was added. The mixture was finally cooled to roomtemperature. A 500 μL aliquot was evaporated to dryness, weighed (246mg) to determine that the concentration of catalyst was 1.8 M.

[0642] 5-(2-Bromo-1-oxy)ethyl-8-benzyloxy-2(1H)-quinolinone (R) (90.0 g,243 mmol) was placed under nitrogen, tetrahydrofuran (900 mL) was addedfollowed by the catalyst from above (1.8 M in toluene, 15 mL, 27 mmol).The suspension was cooled to −10±5° C. in an ice/isopropanol bath.Borane (1.0 M in THF, 294 mL, 294 mmol) was added over 4 hours. Thereaction was stirred an additional 45 minutes at −10° C., then methanol(250 mL) was added slowly. The mixture was concentrated under vacuum.The residue was dissolved in boiling acetonitrile (1.3 L), filteredwhile hot and cooled to room temperature. The crystals were filtered,washed with acetonitrile and dried under reduced pressure to give5-(2-bromo-(R)-1-hydroxy)ethyl-8-benzyloxy-2(1H)-quinolinone (FF) (72.5g, 196 mmol, 81% yield, 95% ee, 95% pure by HPLC area ratio).

[0643] b. Synthesis of5-(2-bromo-(R)-1-tert-butyldimethylsiloxy)ethyl-8-benzyloxy-2(1H)-quinolinone(HH)

[0644] Compound FF (70.2 g, 189 mmol) was treated withN,N-dimethylformamide (260 mL) and cooled in an ice bath under nitrogen.2,6-Lutidine (40.3 g, 376 mmol) was added over 5 minutes followed slowlyby tert-butyldimethylsilyl trifluoromethanesulfonate (99.8 g, 378 mmol),keeping the temperature below 20° C. The mixture was allowed to warm toroom temperature for 45 minutes. Methanol (45 mL) was added to themixture dropwise over 10 minutes and the mixture was partitioned betweenethyl acetate/cyclohexane(1:1,500 mL) and water/brine (1:1,500 mL). Theorganics were washed twice more with water/brine (1:1,500 mL each). Thecombined organics were evaporated under reduced pressure to give a lightyellow oil. Two separate portions of cyclohexane (400 mL) were added tothe oil and distillation continued until a thick white slurry wasformed. Cyclohexane (300 mL) was added to the slurry and the resultingwhite crystals were filtered, washed with cyclohexane (300 mL) and driedunder reduced pressure to give5-(2-bromo-(R)-1-tert-butyldimethylsiloxy)ethyl-8-benzyloxy-2(1H)-quinolinone(HH) (75.4 g, 151 mmol, 80% yield, 98.6% ee).

[0645] c. Synthesis ofN-{2-(4-bromophenyl)ethyl}-(R)-2-tert-butyldimethylsiloxy-2-(8-benzyloxy-2(1H)-quinolinon-5-yl)ethylamine(JJ)

[0646] Compound HH (136.5 g, 279 mmol), 4-bromophenethylamine (123 g,615 mmol) and dimethyl sulfoxide (180 mL) were mixed at room temperatureunder nitrogen. Another 40 mL of dimethyl sulfoxide was added. Themixture was heated to 85° C. for 5 hours. The reaction was partitionedbetween ethyl acetate (1 L) and 10% aqueous acetic acid (500 mL). Theorganics were washed with 10% aqueous acetic acid (3×500 mL), then with1N sodium hydroxide (3×500 mL). The last wash was filtered throughCelite (100 g). The organic layer was concentrated to 300 mL andcyclohexane (2×500 mL) was added and the solution concentrated to 300mL. Sufficient cyclohexane was added to form 1.8 L final volume whichwas filtered through Celite (50 g). A solution of HCl in isopropanol,prepared by slowly adding concentrated HCl (23.5 mL) to isopropanol (180mL) at 10° C. (internal), was added to the crude product and thereaction mixture was stirred for 5 hours, washed with cyclohexane (2×500mL) and dried under reduced pressure for 24 hours to giveN-[2-(4-bromophenyl)ethyl}-(R)-2-tert-butyldimethylsiloxy-2-(8-benzyloxy-2(1H)-quinolinon-5-yl)ethylamine(JJ) hydrochloride (145 g, 80 mol %, 106 wt %, HPLC purity 97.9%).

[0647] d. Synthesis ofN-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-tert-butyldimethylsilyl-2-(8-benzyloxy-2(1H)-quinolinon-5-yl)ethylamine(NN)

[0648] To compound JJ hydrochloride (73.7 g, 114 mmol) and4-methoxy-3-phenylaniline hydrochloride (32.4 g, 137 mmol), toluene (380mL) was added with mild agitation for 5 minutes, followed by sodiumtert-butoxide (49.3 g, 513 mmol) in portions over 1 minute, and finally2,2′-bis(diphenylphosphino)-11β-binaphthyl (10.65 g, 17 mmol) andtris(dibenzylideneacetone)dipalladium(0) (5.22 g, 5.7 mmol). Theresulting mixture was stirred and heated to 85-89° C. (internal) for 2.5hours. The solution was cooled to room temperature, water (400 mL) wasadded and the mixture was stirred for 5 minutes, filtered through Celite(80 g), and partitioned with toluene (100 mL). The organic layer wascollected and concentrated under reduced pressure in a 40° C. bath togiveN-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-tert-butyldimethylsilyl-2-(8-benzyloxy-2(1H)-quinolinon-5-yl)ethylamine(NN) as a dark viscous oil.

[0649] e. Synthesis ofN-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-benzyloxy-2(1H)-quinolinon-5-yl)ethylamine(PP)

[0650] Compound NN from the previous step was dissolved in 280 ml ofTHF. Triethylamine trihydrofluoride (27.6 g, 171 mmol) was added to thesolution, an additional 20 mL of THF was used to rinse down residualreagent, and the reaction was stirred at 25° C. under nitrogen for 16hours. The reaction mixture was concentrated under reduced pressure in a25° C. bath to give a dark viscous oil to which dichloromethane (400 mL)was added, followed by 1N aqueous NaOH (200 mL). The reaction mixturewas stirred for 5 hours. The top layer was discarded and the organiclayer was concentrated to a viscous oil.

[0651] The oil was dissolved in dichloromethane to give a total volumeof 630 mL. A 60 mL aliquot was taken and concentrated to 30 mL. Toluene(60 mL) was added, followed by a mixture of concentrated hydrochloricacid (2.7 mL) and methanol (4.5 mL) to give a thick paste covered in afree-flowing liquid. The liquid was carefully removed and the pastewashed with toluene (50 mL). The gum was partitioned betweendichloromethane (40 mL) and 1N aqueous sodium hydroxide (40 mL) and theorganic solvents were removed under reduced pressure. The residue waspurified chromatographically over silica using a gradient of 0-10%methanol in dichloromethane to giveN-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-benzyloxy-2(1H)-quinolinon-5-yl)ethylamine(PP). (98.6% pure by HPLC area ratio)

[0652] f. Purification ofN-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl)—(R)-2-hydroxy-2-(8-benzyloxy-2(1H)-quinolinon-5-yl)ethylamine (PP)

[0653] Intermediate PP (0.5 g, 0.82 mmol, Pd level 850 ppm by ICP) wasdissolved in 1:1 dichloromethane:methanol (5 mL) and 4M hydrochloricacid in dioxane (0.445 mL, 1.78 mmol) was added. The resulting darkbrown solution was diluted further with dichloromethane (7.5 ntL) and3-(1-thioureido)propyl functionalized silica gel (0.05 g) was added(Sigma-Aldrich, St. Louis, Mo.). The suspension was stirred at roomtemperature for 20 h followed by filtration through filter paper. Theremaining yellow silica was washed with a mixture of 5 mL of methanoland 30 mL of dichloromethane. Combined organic solutions were washedwith saturated aqueous sodium bicarbonate (50 mL) and brine(50 mL). Theorganic solution was treated with anhydrous sodium sulfate for 30minutes, filtered and evaporated under reduced pressure to giveN-{2-[4-(3-phenyl-4methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-benzyloxy-2(1H)-quinolinon-5-yl)ethylamine(PP) (90% yield, Pd level by ICP 30 ppm, purity 97.4% by HPLC arearatio).

[0654] g. Synthesis ofN-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine(61) hydrochloride

[0655] To compound PP from the previous step (2.1 g, 3.43 mmol) wasadded under nitrogen 10% palladium on carbon (420 mg) followed byethylene glycol (16 mL) and concentrated hydrochloric acid (0.57 mL, 6.9mmol). The suspension was stirred vigorously under 1 atmosphere ofhydrogen for 5 h. The solids were filtered off and washed with ethyleneglycol (5 mL). The filtrate was warmed to 50° C. and water (21 mL) wasadded over 5 minutes under stirring. A brown gum formed which broke upto an off-white solid under continued stirring at 50° C. for 40 min. Thesolid was filtered off, washed with water (2×20 mL) and air dried toafford an amorphous hydrochloride salt of compound 61 (2.5 g containing44.3% water, 74% yield) To improve the purity of the title compound,(2.5 g, 4.8 mmol) was dissolved in methanol (25 mL) at 40° C. The darkblue solution was cooled to room temperature, decolorizing charcoal(Darco-KB, 2.5 g) was added and the suspension stirred at roomtemperature overnight. Solids were filtered off over Celite (2.0 g),filter cake was washed with methanol (2×IO mL) and solvent wasevaporated under reduced pressure to leave an amorphous hydrochloridesalt ofN-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine(61) as a light gray solid (1.5 g)

Example 62 Synthesis of Compound 62

[0656]

[0657] To a solution of 70 mg of compound nn (0.09 mmol) in 5 mL ofglacial acetic acid was added 21 mg of 10% palladium on carbon. Thereaction was shaken under an atmosphere of H₂ at 40 psi. After 18 h, thereaction was filtered and the filtrate purified by reversed-phase HPLC(gradient of 10 to 50% acetonitrile in 0.1% aqueous TFA) to affordcompound 62 (10 mg, 0.0126 mmol) as the TFA salt. ¹H NMR (300 MHz,DMSO-d₆) δ 1.21-1.33 (m, 2H), 1.39-1.52 (m, 4H), 2.74 (m, 4H), 2.82 (m,2H), 2.96-3.20 (m, 4H), 5.25 (m, 1H), 6.13 (m, 1H), 6.51 (m, 1H), 6.90(d, 1H, J=8.2 Hz), 7.01 (d, 2H, J=8.8 Hz), 7.07-7.15 (m, 5H), 7.43 (d,2H, J=9.1 Hz), 8.07 (d, 2H, J=9.9 Hz), 8.61 (br s, 2H), 8.76 (s, 1H),10.39 (s, 1H), 10.46 (s, 1H). m/z: [M+H⁺] calcd for C₃₀H₃₄N₄O₅S 563.7;found 563.3.

[0658] The intermediate compound nn was prepared as follows.

[0659] a. Synthesis of Compound kk.

[0660] To a flask containing 4.51 g (11.6 mmol) of compound B (Example13, part b), 3.61 g (15.0 mmol) of 4-(piperdinosulfonyl)aniline(available from Maybridge), 0.53 g (0.58 mmol) oftris(dibenzylidineacetone)dipalladium(0), 1.19 g (1.91 mmol) ofracemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, and 1.45 g (15.1mmol) of sodium tert-butoxide was added toluene (60 mL), and the mixturewas stirred at 95° C. for 6 h under a nitrogen atmosphere. The mixturewas diluted with 200 mL diethyl ether and washed twice with 100 mLportions of 1.0 M aqueous NaHSO₄, followed by 100 mL of saturatedaqueous NaHCO₃. The diethyl ether phase was dried over MgSO₄, filtered,and concentrated to a dark oil. The oil was purified by silica gelchromatography (gradient of 30 to 40% ethyl acetate in hexanes) toafford compound kk as an orange foam.

[0661] b. Synthesis of Compound mm.

[0662] A solution of compound kk (2.88 g, 5.24 mmol) in 20 mL CH₂Cl₂ wascooled to 0° C. and 20 mL of TFA was added. After 20 min, the reactionwas concentrated and the residue dissolved in isopropyl acetate. Theisopropyl acetate solution was washed twice with 1.0 N aqueous NaOHfollowed by water and then dried over MgSO₄, filtered and concentratedto an oil. The oil was dissolved in 2 mL DMF and intermediate AA (337mg, 0.69 mmol), diethyl isopropyl amine (179 mg, 1.38 mmol) andpotassium iodide (172 mg, 1.04 mmol) were added. The reaction was heatedto 100° C. After 18 h, the reaction was cooled and added to vigorouslystirred ice water. Compound mm precipitated, was isolated by filtrationand purified by silica gel chromatography (1:1 ethyl acetate/hexanes) toafford 544 mg solid.

[0663] c. Synthesis of Compound nn.

[0664] To a solution of compound mm (83 mg, 0.01 mmol) in CH₂Cl₂ (0.9mL) and triethylamine (0.09 mL) was added triethylamine trihydrofluoride(313 mg, 1.94 mmol). The solution was stirred at room temperature undera N₂ atmosphere. After 18 h, the reaction mixture was diluted withCH₂Cl₂ and washed with 1.0 N aqueous HCl, followed by two washes withsaturated NaCl solution. The organic phase was dried over MgSO₄,filtered and concentrated under reduced pressure to afford compound nn(70 mg).

Example 63 Synthesis of Compound 63

[0665]

[0666] To a solution of 730 mg of compound rr (1.05 mmol) in 10 mL ofglacial acetic acid was added 100 mg of 10% palladium on carbon. Thereaction was stirred under an atmosphere of H₂. After 65 h, the reactionwas filtered and the filtrate purified by reversed-phase HPLC (gradientof 10 to 50% acetonitrile in 0.1% aqueous TFA) to afford 90 mg (0.14mmol) the TFA salt. The TFA salt product was solubilized inacetonitrile/water (1:2, 10 mL) to which 3 mL of 0.1 N aqueous HCl wasadded. The solution was frozen and lyophilized to afford compound 63 asan HCl salt. m/z: [M+H⁺] calcd for C₂₉H₂₉N₅O₄ 512.6; found 512.3.

[0667] Intermediate rr was prepared as follows.

[0668] a. Synthesis of Compound qq

[0669] To 0.99 g of compound cc (Example 60, part a) (1.99 mmol) in 5 mLCH₂Cl₂ was added 2 mL TFA. After 1 h, the solution was concentrated,diluted with 15 mL CH₂Cl₂ and washed with 1.0 N aqueous sodiumhydroxide. The aqueous was collected and washed again with CH₂Cl₂ (10mL) followed by a wash with ethyl acetate (10 mL). The organic layerswere combined and dried over MgSO₄, filtered, and concentrated underreduced pressure. The crude product was purified by silica gelchromatography (gradient of 2-10% MeOH in CH₂Cl₂) to afford intermediateqq as an oil.

[0670] a. Synthesis of Compound rr.

[0671] To a solution of compound qq (2.0 g, 5.0 mmol) in 27 mL DMF wereadded bromoketone R (from Example 56, part a) (1.71 g, 4.5 mmol) andK₂CO₃ (1.91 g, 13.8 mmol). The reaction was heated to 50° C. After 1 h,the reaction was allowed to cool to room temperature and the K₂CO₃ wasfiltered off. The filtrate was diluted with CH₂Cl₂ (50 mL) and waswashed with 0.1N HCl (30 mL). The organic layer was washed once withsaturated sodium bicarbonate solution, followed by aqueous saturatedsodium chloride, dried over Na₂SO₄ and concentrated under reducedpressure to afford an oil. The product (1.14 g, 1.65 mmol) wassolubilized in 12 mL THF/EtOH (1:1) and NaBH₄ (380 mg, 10.0 mmol) wasadded. After 20 minutes of vigorous stirring. The reaction was quenchedwith saturated aqueous NH₄Cl which was added until effervescence of thereaction mixture ceased. The reaction mixture was partitioned betweenethyl acetate and saturated sodium bicarbonate solution. The organiclayer was washed twice with saturated sodium bicarbonate, followed bysaturated sodium chloride, dried over Na₂SO₄ and concentrated underreduced pressure. The crude product was purified by silica gelchromatography (2% MeOH in CH₂Cl₂) to yield 230 mg of intermediate rr.

Example 64 Synthesis ofN-{2-[4-(4-ethoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine(64)

[0672]

[0673] To a mixture of 580 mg (0.93 mmol) of compound V in 25 mL ofethanol was added 173 mg of 10% palladium on carbon under a stream ofnitrogen. The flask was fitted with a balloon of hydrogen gas, and thereaction was vigorously stirred for 4 days. The reaction was filteredand the filtrate was concentrated under reduced pressure. The residuewas purified by reverse phase HPLC using a gradient of 10 to 50%acetonitrile in 0.1% aqueous TFA. Fractions containing pure product werecombined and lyophilized to afford a TFA salt of compound 64 as anoff-white powder.

[0674] A sample of the TFA salt of compound 64 (150 mg) was dissolved inacetonitrile (2.0 mL) and water (2.0 mL). 0.1N HCl (7.0 mL, 0.70 mmol)was added, and the resulting precipitate was redissolved by the additionof acetonitrile. The resulting solution was lyophilized to give a solidwhich was again dissolved in acetonitrile (5.0 mL) and water (5.0 mL).0.1N HCl (7.0mL, 0.7 mmol) was added and the resulting solution waslyophilized to give a hydrochloride salt of compound 64 as an off whitepowder. ¹H NMR (300 MHz, DMSO-d6) δ 10.10 (br s, 1H), 9.62 (s, l1H),8.80 (br s, 1H), 8.65 (br s, 1H), 8.27 (d, 1H), 8.15 (d, 1H), 6.80-7.15(m, 11H), 4.78 (dd, 1H), 3.94 (quar, 2H), 2.80-3.15 (m, 6H), 1.29 (t,3H); m/z: [M+H⁺] calcd for C₂₅H₂₉N₃O₄ 436.22; found 436.3.

[0675] The intermediate compound V was prepared as follows.

[0676] a. Synthesis of Compound V.

[0677] To 0.60 g (1.3 mmol) of compound C (Example 37, part a) in 20 mLof CH₂Cl₂ at 0° C. was added 2.0 mL of trifluoroacetic acid. After 1 h,the solution was concentrated under reduced pressure, and the residuewas partitioned between 1.0 M aqueous NaOH and EtOAc. The phases wereseparated, and the EtOAc phase was dried over MgSO₄, filtered, andconcentrated to an oil and dissolved in 10 mL of 1:1 methanol:THF.Bromohydrin GG (Example 13, part d) (360 mg, 1.0 mmol) and K₂CO₃ (380mg, 2.7 mmol) were added and the reaction was stirred at roomtemperature for 1.5 h. The reaction was diluted with 30 mL water andextracted twice with 30 mL portions of toluene. The toluene extractswere combined, dried over MgSO₄, filtered, and concentrated. The residuewas heated to 120° C. After 2 h, the residue was cooled to roomtemperature and purified by silica gel chromatography (gradient of 5 to10% methanol in CH₂Cl₂). Fractions containing pure product were combinedand concentrated to afford compound V as a tan solid.

Example 65 Synthesis ofN-{2-[4-(3-phenylphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine(65)

[0678]

[0679] Compound W (55.2 mg, 0.094 mmol), phenyl boronic acid (13.2 mg,0.113 mmol) and [1,1′-bis(diphenylphosphinoferrocene)dichloropalladium(II), complex with dichloromethane (PdCl₂(dppf)-DCM) (5.0 mg, 0.006mmol) were combined in a small pressure tube and purged with N₂.1,2-Dimethoxyethane (1.0 mL) and 2.0 N cesium carbonate (150 μL, 0.3mmol) were added. The tube was seated, and then placed in an oil bath at90° C. for 4 hours. The solution was then cooled to room temperature andDCM (10 mL) was added. The solution was filtered and concentrated todryness. To the residue there was added DMF (1.0 mL), 10% Pd/C (100 mg)and ammonium formate (200 mg) and the solution was heated to 50° C. for1.5 hours. At this time, water:acetonitrile 1:1 and 200 μL TFA was addedand the solution was filtered to remove the catalyst. The filtrate waspurified by reverse phase HPLC. Fractions containing pure product werecombined and lyophilized to give compound 65 as a TFA salt. ¹H NMR (300MHz, DMSO-d6) δ 10.46 (s, 1H), 10.39 (s, 1H), 8.60 (br s, 2H), 8.19 (s,1H), 8.07 (d, 1H), 7.50 (d, 2H), 7.37 (t, 2H) 7.15-7.30 (m, 3H),6.85-7.10 (m, 9H), 6.51 (dd, 1H), 6.11 (d, 1H), 5.23 (d, 1H), 2.70-3.15(m, 6H); m/z: [M+H⁺] calcd for C₃₁H₂₉N₃O₃ 492.23; found 492.3.

[0680] a. Synthesis of Compound U

[0681] Compound HH (Example 61B, part f) (9.1 g, 18.62 mmol),4-aminophenethylamine (9.8 mL, 74.8 mmol) and sodium iodide (4.2 g,27.93 mmol) were placed in a flask and purged with nitrogen. Methylsulfoxide (25 mL) was added, and the solution was placed in an oil bathheated at 140° C. The solution was the stirred for 20 min at 140° C. Thereaction was allowed to cool to room temperature, then ethyl acetate(300 nL) and H₂O (300 mL) were added. The phases were partitioned, andthe organic layer was washed with water (4×200 mL) and saturated sodiumchloride (4×200 mL). The organic phase was dried over sodium sulfate,filtered and concentrated under vacuum to yield compound U (10.5 g).

[0682] b. Synthesis of Compound W

[0683] Compound U (5.18 g, 9.53 mmol),tris(dibenzylideneacetone)dipalladium(0) (0.44 g, 0.48 mmol),2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.63 g, 0.95 mmol), andsodium t-butoxide (1.83 g, 19.06 mmol) were combined in a flask andpurged with nitrogen. 1-Bromo-3-iodobenzene (2.0 mL, 11.44 mmol) wasadded and the flask was purged again. o-Xylene (50 ntL) was added, andthe solution was heated at reflux under nitrogen for 2.5 hours, at whichtime HPLC analysis indicated complete reaction. The o-xylene was removedunder vacuum with heating, and dichloromethane (200 mL) was added. Oncethe residue was dissolved, celite (30 g) was added, and the mixture wasfiltered and filter cake was washed with dichloromethane until all ofthe product was collected. The solution was concentrated to drynessunder vacuum, redissolved in THF (20 mL), and purged with nitrogen.Tetrabutylammonium fluoride (20 mL, 1.0 M in THF, 20 mmol) was added viasyringe, and the solution was stirred for 18 hours at room temperature.The THF was then removed, and the residue was dissolved in DCM, andwashed with water (1×200 mL) and half-saturated sodium chloride (I x 200mL). The organic phase was dried over sodium sulfate, concentrated andchromatographed over silica gel (50 g, 0-10% MeOH in dichloromethane) toyield compound W as a yellow solid.

[0684] Synthesis of Compounds of Formula (X)—Compounds 66-93:

Examples 66-69 Synthesis of Compounds 66-69

[0685] Using procedures similar to that described in Example 65, exceptreplacing the phenylboronic acid with the appropriate substitutedphenylboronic acid, TFA salts of compounds 66-69 were prepared.

[0686] Compound 66:N-{2-[4-(3-(2-chlorophenyl)phenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(11H)-quinolinon-5-yl)ethylamine(Formula (X) where R¹¹ is 2-chlorophenyl): ¹H NMR (300 MHz, DMSO-d6) δ10.47 (s, 1H), 10.37 (s, 1H), 8.55, (br s, 2H), 8.22, (s, 1H), 8.06 (d,1H)7.46 (m, 1H), 7.32 (m, 3H), 7.22 (t, 1H), 7.01 (m, 8H), 6.89 (d, 1H),6.74 (dd, 1H), 6.51 (d, 1H), 6.10 (d, 1H), 3.18 (m, 4H), 2.80 (m, 2H);m/z: [M+H⁺] calcd for C₃₁H₂₈ClN₃O₃ 526.19; found 526.4.

[0687] Compound 67:N-{2-[4-(3-(2-methoxyphenyl)phenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine(Formula (X) where R¹¹ is 2-methoxyphenyl): ¹H NMR (300 MHz, DMSO-d6) δ10.46 (s, 1H), 10.40 (s, 1H), 8.60 (brs, 2H), 8.12 (s, 1H), 8.06 (d,1H), 7.16 (m, 13H), 6.80 (d, 1H), 6.51 (d, 1H) 6.11 (s, 1H) 5.24 (d,1H), 3.69 (s, 3H), 3.10 (m, 4H), 2.80 (m, 2H); m/z: [M+H⁺] calcd forC₃₂H₃₁N₃O₄ 522.24; found 522.7.

[0688] Compound 68: Formula (X) where R¹¹ is 4-hydroxymethylphenyl: ¹HNMR (300 MHz, DMSO-d6) δ 10.47 (s, 1H), 10.39 (s, 1H), 8.60 (br s, 2H),8.18 (s, 1H), 8.07 (d, 1H), 7.46 (d, 2H), 7.30 (d, 2H), 7.20 (m, 2H),7.00 (m, 8H), 6.51 (dd, 1H), 6.11 (s, 1H), 5.23 (d, 1H), 4.44 (s, 2H),3.10 (m, 4H), 2.80 (m, 2H); m/z: [M+H⁺] calcd for C₃₂H₃₁N₃O₄ 522.24;found 522.4.

[0689] Compound 69: Formula (X) where R¹¹ is 4-methoxyphenyl: ¹H NMR(300 MHz, DMSO-d6) δ 10.47 (s, 1H), 10.39 (s, 1H) 8.60 (br s, 2H), 8.16(s, 1H), 8.07 (d, 1H), 7.44 (d, 2H), 6.85-7.20 (m, 12H), 6.51 (dd, 1H),6.12 (d, 1H), 5.23 (d, 1H), 3.70 (s, 3H), 3.10 (m, 4H), 2.80 (m, 2H);m/z: [M+H⁺] calcd for C₃₂H₃₁N₃O₄ 522.24; found 522.4.

Example 70 Synthesis of Compound 70

[0690] Compound 70: Formula (X) where R¹¹ is 4-chlorophenyl

[0691] Compound W (84.0 mg, 0.143 mmol), 4-chlorophenyl boronic acid(27.2 mg, 0.172 mmol) and[1,1′-bis(diphenylphosphinoferrocene)dichloropalladium (II), complexwith dichloromethane (PdCl₂(dppf)-DCM) (5.9 mg, 0.007 mmol) werecombined in a small pressure tube and purged with N₂.1,2-Dimethoxyethane (2.0 mL) and 2.0 N cesium carbonate (150 uL, 0.3mmol) were added. The tube was sealed, and then placed in an oil bath at90° C. for 4 hours. The solution was then cooled to room temperature andDCM (10 mL) was added. The solution was filtered and concentrated todryness. To the residue there was added DMF (1.0 mL) and 10% palladiumon carbon (10 mg), and the reaction was stirred under one atmosphere ofhydrogen for 4 hours. At this time, water:acetonitrile 1:1 and 200 uLTFA was added and the solution was filtered to remove the catalyst. Thefiltrate was purified by reverse phase HPLC. Fractions containing pureproduct were combined and lyophilized to give compound 70 as a TFA salt.¹H NMR (300 MHz, DMSO-d6) δ 10.46 (s, 1H), 10.40 (s, 1H), 8.61 (br s,2H), 8.22 (s, 1H), 8.07 (d, 1H), 7.53 (d, 2H), 7.42 (d, 2H), 7.23 (t,1H), 7.14 (s, 1H), 6.85-7.10 (m, 8H), 6.51 (d, 1H), 6.12 (s, 1H), 5.24(d, 1H), 3.10 (m, 4H), 2.80 (m, 2H); m/z: [M+H⁺] calcd for C₃₁H₂₈ClN₃O₃526.19; found 526.4.

Examples 71-72 Synthesis of Compounds 71-72

[0692] Using procedures similar to that described in Example 70, exceptreplacing the 4-chlorophenylboronic acid with the appropriatesubstituted boronic acid, TFA salts of compounds 71-72 were prepared.

[0693] Compound 71: Formula (X) where R¹¹ is 5-indolyl: ¹H NMR (300 MHz,DMSO-d6) δ 11.07 (s, 1H), 10.47 (s, 1H), 10.40 (s, 1H), 8.60 (br s, 2H),8.15 (s, 1H), 8.11 (d, 1H), 7.65 (s, 1H), 7.15-7.40 (m, 5H), 7.00-7.15(m, 5H), 6.89 (d, 2H), 6.51 (dd, 1H), 6.39 (s, 1H), 6.11 (s, 1H), 5.24(d, 1H), 3.10 (m, 4H), 2.80 (m, 2H); m/z: [M+H⁺] calcd for C₃₃H₃₀N₄O₃531.24; found 531.4.

[0694] Compound 72: Formula (X) where R¹¹ is 4-pyridyl: ¹H NMR (300 MHz,DMSO-d6) δ 10.48 (s, 1H) 10.38 (s, 1H), 8.60 (br m, 4H), 8.32 (s, 1H),8.07 (d, 1H), 7.69 (d, 2H), 7.31 (m, 2H), 7.16 (d, 1H) 7.05 (m, 6H),6.90 (d, 1H), 6.52 (dd, 1H), 6.11 (s, 1H), 5.24 (d, 1H), 3.10 (m, 4H),2.80 (m, 2H); m/z: [M+H⁺] calcd for C₃₀H₂₈N₄O₃ 493.23; found 493.5.

Example 73 Synthesis of Compound 73

[0695] Compound 73: Formula (X) where R¹¹ is hydrogen: A TFA salt ofcompound 73 was prepared: ¹H NMR (300 MHz, DMSO-d6) δ 10.48 (s, 1H),10.39 (s, 1H), 8.59 (br s, 2H), 8.07 (dd, 2H), 6.85-7.17 (m, 10H), 6.72(t, 1H), 6.52 (dd, 1H), 6.11 (d, 1H), 5.22 (d, 1H), 3.10 (m, 4H), 2.80(m, 2H); m/z: [M+H⁺] calcd for C₂₅H₂₅N₃O₃ 416.20; found 416.3.

Example 74 Synthesis ofN-{2-[4-(3-(3-cyanophenyl)phenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine(74)

[0696] Compound 74: Formula (X) where R¹¹ is 3-cyanophenyl

[0697] Compound W (Example 65, part b) (58.1 mg, 0.100 mmol),3-cyanophenyl boronic acid (17.6 mg, 0.120 mmol) and[1,1′-bis(diphenylphosphinoferrocene)dichloropalladium (II), complexwith dichloromethane (PdCl₂(dppf)-DCM) (approximately 6 mg, 0.007 mmol)were combined in a small pressure tube and purged with N₂.1,2-Dimethoxyethane (2.0 mL) and 2.0 N cesium carbonate (200 uL, 0.4mmol) were added, the tube was sealed, and then placed in an oil bath at90° C. for 5 hours. The solution was then cooled to room temperature andDCM (10 mL) was added. The solution was dried (Na₂SO₄) for 30 minutes,then filtered, concentrated and dried under vacuum. The residue wasdissolved in DCM (2 mL) and cooled to 0° C., then boron trichloride(1.0N in DCM, 11.0 mL, 11.0 mmol) was added. After 10 minutes thereaction was quenched with methanol (10 mL), and concentrated underreduced pressure. The residue was purified by reverse phase HPLC.Fractions containing pure product were combined and lyophilized to givecompound 74 as a TFA salt. ¹H NMR (300 MHz, DMSO-d6) δ 10.45 (s, 1H),10.40 (s, 1H), 8.70 (br 2, 2H), 8.34 (m, 1H), 8.09 (d, 1H), 7.97 (s,1H), 7.85 (dt, 1H), 7.74 (dt, 1H), 7.58 (t, 1H), 7.20-7.30 (m, 2H),6.95-7.10 (m, 7H), 6.90 (d, 1H), 6.50 (d, 1H), 6.12 (s, 1H), 5.25 (d,1H), 3.10 (m, 4H), 2.80 (m, 2H); m/z: [M+H⁺] calcd for C₃₂H₂₈N₄O₃517.23; found 517.4.

Examples 75-93 Synthesis of Compounds 75-93

[0698] Using procedures similar to that described in Example 74, exceptreplacing the 3-cyanophenyl boronic acid with the appropriatesubstituted boronic acid, TFA salts of compounds 75-93 were prepared.

[0699] Compound 75: Formula (X) where R¹¹ is trans-2-phenylvinyl: m/z:[M+H⁺] calcd for C₃₃H₃₁N₃O₃ 518.25; found 518.3.

[0700] Compound 76:N-{2-[4-(3-(3-pyridyl)phenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine(Formula (X) where R¹¹ is 3-pyridyl):

[0701]¹H NMR (300 MHz, DMSO-d6) δ 10.38 (br s, 2H), 8.84 (s, 2H), 8.67(s, 1H), 8.58 (d, 1H), 8.25 (s, 1H), 8.14 (d, 1H), 8.11 (d, 1H), 7.59(dd, 1H), 7.27 (m, 2H), 7.05 (m, 7H), 6.90 (d, 11H), 6.50 (d, 1H), 5.28(d, 1H), 3.10 (m, 4H), 2.83 (m, 2H). m/z: [M+H⁺] calcd for C₃₀H₂₈N₄O₃493.23; found 493.5.

[0702] Compound 77: Formula (X) where R¹¹ is 4-cyanophenyl: ¹H NMR (300MHz, DMSO-d6) 810.45 (br s, 1H), 10.40 (s, 1H), 8.62 (br, s, 2H), 8.27(s, 1H), 8.07 (d, 1H), 7.84 (d, 2H), 7.72 (d, 2H), 7.27 (m, 2H), 7.18(m, 7H), 6.91 (d, 1H), 6.52 (d, 1H), 6.12 (s, 1H), 5.24 (m, 1H), 3.12(m, 4H), 2.81 (m, 2H). m/z: [M+H⁺] calcd for C₃₂H₂₈N₄O₃ 516.60; found517.4.

[0703] Compound 78: Formula (X) where R¹¹ is 3,5-dimethylisoxazole-4-yl:m/z: [M+H⁺] calcd for C₃₀H₃₀N₄O₄ 511.24; found 511.5.

[0704] Compound 79: Formula (X) where R¹¹ is 2-furanyl: ¹H NMR (300 MHz,DMSO-d6) δ 11.15 (s, 1H), 10.47 (s, 1H), 10.41 (s, 1H), 8.64 (br s, 1H),8.10 (t, 2H), 7.08 (m, 9H), 6.77 (s, 1H), 6.74 (s, 1H), 6.52 (d, 1H),6.30 (s, 1H), 6.12 (s, 1H), 6.02 (q, 1H), 5.25 (d, 1H), 3.10 (m, 4H),2.85 (m, 2H). m/z [M+H⁺] calcd for C₂₉H₂₇N₃O₄ 482.21; found 481.4.

[0705] Compound 80: Formula (X) where R¹¹ is thiophene-2-yl: ¹H NMR (300MHz, DMSO-d6) δ 10.47 (s, 1H), 10.38 (s, 1H), 8.62 (br s, 2H), 8.22 (s,1H), 8.07 (d, 1H), 7.44 (d, 11H), 7.33 (d, 1H), 7.35 (m, 2H), 7.06 (m,7H), 6.90 (d, 2H), 6.50 (d, 11H), 6.10 (d, 11H), 5.23 (m, 1H), 3.10 (m,4H), 2.85 (m, 2H). m/z [M+H⁺] calcd for C₂₉H₂₇N₃O₃S 498.19; found 498.5.

[0706] Compound 81: Formula (X) where R¹¹ is 3-nitrophenyl: m/z: [M+H⁺]calcd for C₃₁H₂₈N₄O₅ 537.22; found 537.3.

[0707] Compound 82: Formula (X) where R¹¹ is 4-formylphenyl: m/z: [M+H⁺]calcd for C₃₂H₂₉N₃O₄ 520.23; found 520.5.

[0708] Compound 83: Formula (X) where R¹¹ is 2-pyrrolyl: Using aprocedure similar to that described in Example 74, except replacing the3-cyanophenylboronic acid with 1-(tert-butoxycarbonyl)pyrrole-2-boronicacid, a TFA salt of compound 83 was prepared. Deprotection of the Bocgroup occurred under reaction conditions. ¹H NMR (300 MHz, DMSO-d6) δ11.13 (s, 1H), 10.46 (s, 1H), 10.37 (s, 1H), 8.58 (br s, 2H), 8.08 (s,1H), 8.05 (s, 1H), 7.05 (m, 9H), 6.75 (s, 1H), 6.73 (s, 1H), 6.51 (d,1H), 6.23 (s, 1H), 6.08 (s, 1H), 6.01 (s, 1H), 5.22 (m, 1H), 3.12 (m,4H), 2.80 (m, 2H). m/z: [M+H⁺] calcd for C₂₉H₂₈N₄O₃ 481.23; found 481.3.

[0709] Compound 84: Formula (X) where R¹¹ is 4-carboxyphenyl: m/z:[M+H⁺] calcd for C₃₂H₂₉N₃O₅ 536.22; found 536.3.

[0710] Compound 85: Formula (X) where R¹¹ is 4-methylsulfonylphenyl: ¹HNMR (300 MHz, DMSO-d6) δ 10.45 (s, 1H), 10.38 (s, 1H), 8.58 (br s, 1H),8.27 (s, 1H), 8.05 (d, 1H), 7.90 (d, 2H), 7.77 (d, 2H), 7.26 (m, 2H),7.04 (m, 7H), 6.88 (d, 1H), 6.50 (d, 1H), 6.11 (s, 1H), 5.22 (d, 1H),3.16 (s, 3H), 3.11 (m, 4H), 2.80 (m, 2H). m/z: [M+H⁺] calcd forC₃₂H₃₁N₃O₅S 570.21; found 570.3.

[0711] Compound 86: Formula (X) where R¹¹ is 4-hydroxyphenyl: Using aprocedure similar to that described in Example 74, except replacing the3-cyanophenylboronic acid with 4-benzyloxyphenylboronic acid, a TFA saltof compound 86 was prepared. ¹H NMR (300 MHz, DMSO-d6) δ 10.46 (s, 1H),10.40 (s, 1H), 9.47 (s, 1H), 8.71 (br s, 2H), 8.12 (m, 2H), 7.32 (d,2H), 7.02 (m, 9H), 6.75 (d, 2H), 6.51 (d, 1H), 6.10 (s, 1H), 5.25 (d,1H), 3.10 (m, 4H), 2.80 (m, 2H). m/z: [M+H⁺] calcd for C₃₁H₂₉N₃O₄508.23; found 508.3.

[0712] Compound 87:N-{2-[4-(3-(4-aminomethylphenyl)phenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine(Formula (X) where R¹¹ is 4-(aminomethyl)phenyl): m/z: [M+H⁺] calcd forC₃₂H₃₂N₄O₃ 521.26; found 521.3.

[0713] Compound 88: Formula (X) where R¹¹ is 4-ethoxyphenyl: m/z: [M+H⁺]calcd for C₃₃H₃₃N₃O₄ 536.26; found 536.3.

[0714] Compound 89: Formula (X) where R¹¹ is thiophene-3-yl: m/z: [M+H⁺]calcd for C₂₉H₂₇N₃O₃S 498.19; found 498.3.

[0715] Compound 90: Formula (X) where R¹¹ is 2-indolyl: m/z: [M+H⁺]calcd for C₃₃H₃₀N₄O₃ 531.24; found 531.3.

[0716] Compound 91:N-{2-[4-(3-(3-chlorophenyl)phenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine(Formula (X) where R¹¹ is 3-chlorophenyl): ¹H NMR (300 MHz, DMSO-d6) δ10.45 (s, 1H), 10.38 (s, 1H), 8.58 (br s, 2H), 8.20 (s, 1H), 8.06 (d,1H), 7.21 (m, 14H), 6.51 (d, 1H), 6.10 (s, 1H), 5.23 (d, 1H), 3.10 (m,4H), 2.80 (m, 2H). [M+H] calcd for C₃₁H₂₈ClN₃O₃ 526.03; found 526.3.

[0717] Compound 92: Formula (X) where R¹¹ is 3-methoxyphenyl: m/z: [M+H]calcd for C₃₂H₃₁N₃O₄522.24; found 522.0.

[0718] Compound 93: Formula (X) where R¹¹ is 3-fluorophenyl: ¹H NMR (300MHz, DMSO-d6) δ 10.42 (s, 1H), 10.39 (s, 1H), 8.60 (br s, 2H), 8.20 (s,1H), 8.15 (d, 1H), 7.2 (m, 14H), 6.51 (d, 1H), 6.11 (s, 1H), 5.23 (d,1H), 3.10 (m, 4H), 2.81 (m, 2H). m/z: [M+H⁺] calcd for C₃₁H₂₈FN₃O₃509.58; found 510.3.

[0719] Synthesis of Compounds of Formula (XI)—Compounds 94-101

Example 94 Synthesis ofN-{2-[4-(3-(3-pyridyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine(94)

[0720] Compound 94: Formula (XI) where R¹¹ is 3-pyridyl

[0721] a. Synthesis of 4-iodophenethylamine

[0722] 4-Iodophenylacetonitrile (4.80 g, 19.7 mmol) was dissolved intetrahydrofuran (25 mL) under nitrogen, and 1.0 M borane intetrahydrofuran (29.6 mL, 29.6 mmol) was added via syringe. The reactionwas heated at reflux for 1 hour, then cooled in ice and the excessborane was quenched by the addition of methanol (100 mL). When hydrogenevolution ceased, the solvents were removed under reduced pressure. Theresidue was dissolved in tetrahydrofuran (25 mL) and 4N HCl in dioxane(6.0 mL, 24 mmol) was added, followed by ether (75 mL). Thehydrochloride salt of 4-iodophenethylamine was collected on a Buchnerfunnel, washed with ether (2×50 mL) and dried under reduced pressure. Togenerate the free base, the solid was partitioned betweendichloromethane (200 mL) and 1N NaOH (100 mL). The aqueous layer wasextracted with dichloromethane (2×100 mL). The combined organic layerswere dried (Na₂SO₄) and concentrated to give 4-iodophenethylamine (4.52g) as a colorless oil.

[0723] b. Synthesis of Compound QQ

[0724] To a solution of 4-iodophenethylamine (4.5 g, 22 mmol) in methylsulfoxide (13 mL) under nitrogen was added compound HH (from Example 61Bpart f) (7.3 g, 15 mmol), sodium bicarbonate (3.7 g, 44 mmol) and sodiumiodide (3.3 g, 22 mmol). The mixture was heated at 140° C. in an oilbath for 25 minutes. After cooling to room temperature, water (100 mL)was added and the resulting mixture was extracted with ethyl acetate(2×150 mL). The combined extracts were washed with 1N HCl (2×50 mL),water (50 mL) 10% sodium thiosulfate (50 mL), saturated sodiumbicarbonate (50 mL) and brine (50 mL). The solution was dried (Na₂SO₄)and concentrated. The crude product was purified in two lots by flashchromatography on silica gel (75 g) eluting with 0-5% methanol indichloromethane containing 0.5% triethylamine. Compound QQ (6.1 g) wasisolated as a dark yellow oil.

[0725] c. Synthesis of 4-amino-2-bromoanisole

[0726] To a mixture of 2-bromo-4-nitroanisole (5.0 g, 21.5 mmol,Lancaster), ethanol (25 mL) and water (25 mL), was added powdered iron(4.8 g, 86 mmol) and 12 N HCl (0.5 mL). The solution was heated atreflux for 20 minutes. 1N NaOH (10 mL) was added and the reactionmixture was filtered through a pad of celite while still hot, and thenrinsed with ethanol (2×50 mL). The ethanol was removed under reducedpressure and the residue extracted with dichloromethane (2×100 mL). Theorganic extracts were dried (Na₂SO₄) and concentrated. The crude productwas purified by flash chromatography on silica gel (75 g) eluting withdichloromethane, to give 4-amino-2-bromoanisole as a light tan solid.

[0727] d. Synthesis of Compound RR

[0728] A flask containing compound QQ (0.966 g, 1.48 mmol),4-amino-2-bromoanisole (0.35 g, 1.78 mmol),tris(dibenzylidineacetone)dipalladium(0) (0.068 g, 0.074 mmol), BINAP(0.092 g, 0.148 mmol), and sodium tert-butoxide (0.569 g, 5.92 mmol) wasflushed with nitrogen, and then anhydrous o-xylene (30 mL) was added.The mixture was heated at 115° C. in an oil bath for two hours. At thistime, the reaction was cooled to room temperature and the solvent wasremoved under reduced pressure. The brownish residue was redissolved indichloromethane and filtered through a bed of celite. The filtrate wasconcentrated to dryness under reduced pressure, dissolved in THF (20 mL)and purged with nitrogen. Tetrabutylammonium fluoride (1.0 N in THF, 4.5mL, 4.5 mmol) was added and the solution was stirred for 18 hours atroom temperature. The solvent was removed under reduced pressure, andthe residue partitioned between water and DCM. The organic layer waswashed with saturated sodium bicarbonate and brine, dried over sodiumsulfate and concentrated under reduced pressure. The crude product waspurified by flash chromatography on silica gel (1-10% MeOH in DCM) togive compound RR.

[0729] e. Synthesis of Compound 94

[0730] Into a nitrogen purged test tube with a screw cap was placedcompound RR (73 mg, 0.12 mmol),[1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II)dichloromethane complex (10 mg) and 3-pyridylboronic acid (18 mg, 0.14mmol). Dimethoxyethane (2.5 mL) was added, followed by 2.0 N cesiumcarbonate (0.20 mL, 0.40 mmol). The mixture was heated at 90° C. for 4hours. The solution was then cooled to room temperature and DCM (20 mL)was added. The solution was dried (Na₂SO₄) for 30 minutes, thenfiltered, concentrated and dried under vacuum. The residue was dissolvedin DCM (2 mL) and cooled to 0° C., and then boron trichloride (1.0N inDCM, 1.0 mL, 1.0 mmol) was added. After 10 minutes the reaction wasquenched with methanol (10 mL), and concentrated under reduced pressure.The residue was purified by reverse phase HPLC. Fractions containingpure product were combined and lyophilized to give a TFA salt ofN-{2-[4-(3-(3-pyridyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine(94). ¹H NMR (300 MHz, DMSO-d6) δ 10.; m/z: [M+H⁺] calcd for C₃₁H₃₀N₄O₄523.24; found 523.3.

[0731] A sample of the TFA salt (25 mg) was dissolved in acetonitrile(0.5 mL) and water (0.5 mL), followed by 1N HCl (0.10 mL, 0.10 mmol).The solution was lyophylized to a powder which was redissolved inacetonitrile (0.5 mL) and water (0.5 ML). 1N HCl was then added (O. 10mL, 0.10 mmol). Lyophylization gave a hydrochloride salt of compound 94as an off white powder. ¹H NMR (300 MHz, DMSO-d6) δ 10.49 (br s, 1H),9.44 (br s, 1H), 8.97 (d, 1H), 8.78 (d, 1H), 8.77 (br s, 1H), 8.61 (dt,1H), 8.20 (d, 1H), 8.01 (dd, 1H), 6.90-7.15 (m, 8H), 6.47 (d, 1H),5.39(d, 1H), 3.70 (s, 3H), 3.02 (m, 4H), 2.82 (m, 2H); m/z: [M+H⁺] calcd forC₃₁H₃₀N₄O₄ 523.24; found 523.6.

Example 95 Synthesis ofN-{2-[4-(3-(3-cyanophenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine(95)

[0732] Compound 95: Formula (XI) where R¹¹ is 3-cyanophenyl.

[0733] Into a nitrogen purged test tube with a screw cap was placedcompound RR (from Example 94, part d) (100 mg, 0.163 mmol),[1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II)dichloromethane complex (10 mg) and 3-cyanophenylboronic acid (35 mg,0.20 mmol). Dimethoxyethane (3 mL) was added, followed by 2.0 N cesiumcarbonate (0.30 mL, 0.60 mmol). The mixture was heated at 90° C. for 4hours. The solution was then cooled to room temperature and partitionedbetween ethyl acetate and water. The organic layer was dried (Na₂SO₄),concentrated and dried under reduced pressure. The residue was dissolvedin DCM (5 mL) and cooled to 0° C., and then boron trichloride (1.0 N inDCM, 2.0 mL, 2.0 mmol) was added. After 10 minutes the reaction wasquenched with methanol (20 mL), and concentrated under reduced pressure.The residue was purified by reverse phase HPLC. Fractions containingpure product were combined and lyophilized to give a TFA salt ofcompound 95. ¹H NMR (300 MHz, DMSO-d6) δ 10.47 (s, 1H), 10.38 (s, 1H),8.57 (br s, 2H) 8.05 (d, 1H), 7.89 (m, 1H), 7.82 (m, 1H), 7.70 (m, 2H),7.53 (t, 2H), 7.07 (d, 1H), 6.95-7.00 (m, 4H), 6.85-6.92 (m, 3H), 6.50(dd, 1H), 6.09 (d, 1H), 5.22 (d, 1H), 3.65 (s, 3H), 3.10 (m, 4H), 2.80(m, 2H); m/z: [M+H⁺] calcd for C₃₃H₃₀N₄O₄ 547.24; found 547.5.

Examples 96-102 Synthesis of Compounds 96-102

[0734] Using procedures similar to that described in Example 95, exceptreplacing the 3-cyanophenylboronic acid with the appropriate substitutedphenylboronic acid, TFA salts of compounds 96-102 were prepared.

[0735] Compound 96:N-{2-[4-(3-(4-aminomethylphenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine(Formula (XI) where R¹¹ is 4-(aminomethyl)phenyl): ¹H NMR (300 MHz,DMSO-d6) δ 10.47 (s, 1H), 10.40 (s, 1H), 8.58 (br s, 2H), 8.07 (m, 4H),7.87 (s, 1H), 7.40 (dd, 4H), 7.07 (d, 1H), 6.84-7.05 (m, 8H), 6.50 (dd,1H), 6.11 (d, 1H), 5.23 (d, 1H), 3.98 (m, 2H), 3.62 (s, 3H), 3.05 (m,2H), 2.95 (m, 2H), 2.75 (m, 2H); m/z: [M+H⁺] calcd for C₃₃H₃₄N₄O₄551.27; found 551.5.

[0736] Compound 97N-{2-[4-(3-(4-pyridyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine(Formula (XI) where R¹¹ is 4-pyridyl): ¹H NMR (300 MHz, DMSO-d6) δ 10.46(s, 1H), 10.42 (s, 1H), 8.65 (d, 2H), 8.62 (br s, 1H), 8.06 (d, 2H),7.97 (br s, 1H), 7.73 (d, 2H) 6.95-7.10 (m, 7H), 6.90 (dd, 2H), 6.12 (brs, 1H), 5.23 (d, 1H), 3.69 (s, 3H), 3.10 (m, 4H), 2.80 (m, 2H); m/z:[M+H⁺] calcd for C₃₁H₃₀N₄O₄ 523.24; found 523.6.

[0737] Compound 98: Formula (XI) where R¹¹ is 4-formylphenyl: ¹H NMR(300 MHz, DMSO-d6) δ 10.46 (s, 1H), 10.39 (s, 1H), 9.95 (s, 1H), 8.57(br s, 2H), 8.05 (d, 1H), 7.91 (br s, 1H), 7.85 (d, 2H), 7.61 (d, 2H),6.95-7.10 (m, 7H), 6.89 (dd, 2H), 6.50 (dd, 1H), 6.10 (s, 1H), 5.22 (d,1H), 3.65 (s, 3H), 3.05 (m, 4H), 2.75 (m, 2H); m/z: [M+H⁺] calcd forC₃₃H₃₁N₃O₅ 550.24; found 550.6.

[0738] Compound 99: Formula (XI) where R¹¹ is 4-methylsulfonyl: ¹H NMR(300 MHz, DMSO-d6) δ 10.46 (s, 1H), 10.38 (s, 1H), 8.55 (br s, 2H), 8.05(d, 1H), 7.91 (s, 1H), 7.86 (d, 2H), 6.74 (d, 2H), 6.93-7.10 (m, 6H),6.85-6.92 (m, 3H), 6.51 (dd, 1H), 6.09 (d, 1H), 5.22 (d, 1H), 3.65 (s,3H), 3.17 (s, 3H), 3.05 (m, 4H), 2.75 (m, 2H); m/z: [M+H⁺] calcd forC₃₃H₃₃N₃O₆S 600.22; found 600.5.

[0739] Compound 100:N-{2-[4-(3-(4-hydroxyphenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine(Formula (XI) where R¹¹ is 4-hydroxyphenyl): Using a procedure similarto that described in Example 95, except replacing the3-cyanophenylboronic acid with 4-benzyloxyphenylboronic acid, a TFA saltof compound 100 was prepared. ¹H NMR (300 MHz, DMSO-d6) δ 10.46 (s, 1H),10.38 (s, 1H), 9.34 (s, 1H), 8.57 (br s, 2H), 8.06 (d, 1H), 7.80 (s,1H), 7.18 (d, 2H), 7.07 (d, 1H), 6.97 (d, 2H), 6.80-6.90 (m, 6H), 6.69(d, 2H), 6.51 (dd, 1H), 6.09 (s, 1H), 5.23 (d, 1H), 3.60 (s, 3H), 3.05(m, 4H), 2.78 (m, 2H); m/z: [M+H] calcd for C₃₂H₃₁N₃O₅ 538.24; found538.5.

[0740] Compound 101:N-{2-[4-(3-(thiophen-3-yl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine(Formula (XI) where R¹¹ is thiophen-3-yl): ¹H NMR (300 MHz, DMSO-d6) δ10.47 (s, 1H), 10.38 (s, 1H), 8.57 (br s, 2H), 8.06 (d, 1H), 7.83 (s,1H), 6.74 (dd, 1H), 7.48 (dd, 1H), 7.31 (dd, 1H), 7.13 (s, 1H), 7.06 (d,1H), 6.80-7.00 (m, 7H), 6.51 (dd, 1H), 6.01 (s, 1H), 5.23 (d, 1H), 3.70(s, 3H), 3.07 (m, 4H), 2.77 (m, 2H); m/z: [M+H⁺] calcd for C₃₀H₂₉N₃O₄S528.20; found 528.3.

[0741] Compound 102:N-{2-[4-(3-(3-chlorophenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine(Formula (XI) where R¹¹ is 3-chlorophenyl): ¹H NMR (300 MHz, DMSO-d6) δ10.46 (s, 1H), 10.38 (s, 1H), 8.76 (br s, 1H), 8.62 (br s, 1H), 8.10 (s,1H), 7.88 (br s, 1H), 7.15-7.23 (m, 5H), 6.85-7.10 (m, I 1H), 6.50 (d,1H), 6.09 (br s, 1H), 5.27 (d, 1H), 3.65 (s, 3H), 3.10 (m, 4H), 2.80 (m,2H); m/z: [M+H⁺] calcd for C₃₂H₃₀ClN₃O₄ 556.20; found 556.2.

Example 103 Synthesis ofN-{2-[4-(3-(4-(4-morpholino)methylphenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine(103)

[0742] Compound 103: Formula (XI) where R¹¹ is4-(4-morpholino)methylphenyl.

[0743] A trifluoroacetate salt of compound 98 (13 mg, 17 μmol) wasdissolved in N,N-dimethylformamide (75 μL) and morpholine (7.5 uL, 86μmol) added at room temperature. After 5 minutes sodium cyanoborohydride(1.1 mg, 17 μmol) was added followed by methanol (75 μL) and thentrifluoroacetic acid (9.0 μL, 120 μmol). The mixture was kept at roomtemperature for 55 minutes at which point HPLC analysis showed thereaction to be substantially complete. The title compound was purifiedby reverse-phase HPLC. ¹H NMR (300 MHz, DMSO-d6) δ 10.41-10.47 (m, 3H),8.82 (br s, 1H), 8.63 (br s, 1H), 8.10 (d, 1H, J=10.2 Hz), 7.88 (br s,1H), 7.48 (s, 4H), 7.07 (d, 1H, J=8.2 Hz), 6.85-7.0 (m, 8H), 6.50 (d,1H, J=9.9 Hz), 6.11 (br s, 1H), 5.27 (br m, 1H), 4.27 (br s, 2H),3.82-3.93 (br m, 2H), 3.64 (s, 3H), 3.58-3.67 (m, 2H), 3.04 (m, 6H),2.78 (m, 2H); ml/z: [M+H⁺] calcd for C₃₇H₄₀N₄O₅ 621.3; found 621.6

Examples 104-110 Synthesis of Compounds 104-110

[0744] Using procedures similar to that described in Example 74, exceptreplacing the 3-cyanophenyl boronic acid with the appropriatesubstituted boronic acid, TFA salts of compounds 104-110 were prepared.

[0745] Compound 104:N-{2-[4-(3-(2-isopropylphenyl)phenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine(Formula (X) where R¹¹ is 2-isopropylphenyl): m/z: [M+H⁺] calcd forC₃₄H₃₅N₃O₃ 534.3; found 534.5.

[0746] Compound 105:N-{2-[4-(3-(2,6-dimethylphenyl)phenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine(Formula (X) where R¹¹ is 2,6-dimethylphenyl): m/z: [M+H⁺] calcd forC₃₃H₃₃N₃O₃ 520.3; found 520.5.

[0747] Compound 106:N-{2-[4-(3-(2-cyanophenyl)phenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine(Formula (X) where R¹¹ is 2-cyanophenyl): m/z: [M+H⁺] calcd forC₃₂H₂₈N₄O₃ 517.2; found 517.4.

[0748] Compound 107:N-{2-[4-(3-(2-ethoxyphenyl)phenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine(Formula (X) where R¹¹ is 2-ethoxyphenyl): m/z: [M+H⁺] calcd forC₃₃H₃₃N₃O₄ 536.3; found 536.3.

[0749] Compound 108:N-{2-[4-(3-(2-ethoxy-5-chlorophenyl)phenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine(Formula (X) where R¹¹ is 2-ethoxy-5-chlorophenyl): m/z: [M+H⁺] calcdfor C₃₃H₃₂ClN₃O₄ 570.2; found 570.4.

[0750] Compound 109:N-{2-[4-(3-(2-hydroxyphenyl)phenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine(Formula (X) where R¹¹ is 2-hydroxyphenyl): m/z: [M+H⁺] calcd forC₃₁H₂₉N₃O₄ 508.2; found 508.4.

[0751] Compound 110:N-{2-[4-(3-(2-dimethylaminomethylphenyl)phenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine(Formula (X) where R¹¹ is 2-dimethylaminomethylphenyl): m/z: [M+H⁺]calcd for C₃₄H₃₆N₄O₃ 549.3; found 549.3.

Example 111 Synthesis ofN-{2-[4-(3-(3-cyanophenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine(95) andN-12-[4-(3-(3-carbamoylphenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine(111)

[0752] Compound 95: Formula (XI) where R¹¹ is 3-cyanophenyl

[0753] Compound 111: Formula (XI) where R¹¹ is 3-carbamoylphenyl

[0754] Using procedures similar to those described in Example 61C andthe deprotection step of Example 61B, except replacing the4-methoxy-3-phenylaniline hydrochloride with3-(3-cyanophenyl)-4-methoxyaniline in Example 61C, part d, compound 95was prepared. In addition, compound 111 was isolated from the reactionsequence. ¹H NMR (300 MHz, DMSO-d6) δ 10.47 (s, 1H), 10.40 (s, 1H), 8.58(br 2, 2H), 8.06 (d, 1H), 7.94 (s, 1H), 7.86 (s, 2H), 7.73 (d, 1H), 7.54(d, 1H), 7.39 (t, 1H), 7.31 (s, 1H), 7.07 (d, 1H), 6.84-7.00 (m, 9H),6.50 (d, 1H), 6.10 (s, 1H), 5.23 (d, 1H) 3.54 (s, 3H), 3.10 (m, 4H),2.80 (m, 2H); m/z: [M+H⁺] calcd for C₃₃H₃₂N₄O₅ 565.64; found 565.5.

[0755] The intermediate compound 3-(3-cyanophenyl)-4-methoxyaniline wasprepared as follows:

[0756] a. Synthesis of 2-(3-cyanophenyl)-4-nitroanisole

[0757] [1,1′Bis(diphenylphosphino)ferrocene]dichloropalladium(II),complex with dichloromethane(1:1) (1.43 g) was added to a stirredmixture of 3-cyanophenylboronic acid (10.0 g, 61.8 mmol) and2-bromo-4-nitroanisole (14.35 g, 62 mmol) in 2.0N cesium carbonate (92.7mL, 185.4 mmol) and ethylene glycol dimethylether (200 mL). The flaskwas purged with nitrogen and heated at 90° C. (oil bath) for 4 hours.The mixture was allowed to cool to room temperature overnight, duringwhich time the product precipitated from solution. The solid wascollected on a Buchner funnel, washed with water and dried under reducedpressure to give 2-(3-cyanophenyl)-4-nitroanisole (15.7 g).

[0758] b. Synthesis of 3-(3-cyanophenyl)-4-methoxyaniline

[0759] Zinc dust (20.26 g, 310 mmol) was added in portions over fiveminutes to a solution of 2-(3-cyanophenyl)-4-nitroanisole (15.7 g, 62mmol) and ammonium formate (19.48 g, 310 mmol) in methanol (500 mL) andtetrahydofuran (500 mL). The reaction was complete after stirring forone hour at room temperature. The resulting mixture was filtered and thefiltrate was concentrated under reduced pressure. The residue waspurified using flash chromatoghraphy on silica gel eluting with 5%methanol in dichloromethane to give 3-(3-cyanophenyl)-4-methoxyaniline(10 g, 44 mmol) as a yellow oil.

Example 112 Synthesis ofN-{2-[4-(3-(3-aminomethylphenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine(112)

[0760] Compound 112: Formula (XI) where R¹¹ is 3-aminomethylphenyl

[0761] Using procedures similar to those described in Example 61C andthe deprotection step of Example 61B, except replacing the4-methoxy-3-phenylaniline hydrochloride with3-(3-aminomethylphenyl)-4-methoxyaniline in Example 61C, part d, the HClsalt of compound 112 was prepared. ¹H NMR (300 MHz, DMSO-d6) δ 10.54 (s,2H), 9.60 (br s, 1H), 8.85 (br s, 1H), 8.46 (s, 3H), 8.30 (d, 1H), 7.57(s, 1H), 7.44 (m, 3H) 6.90-7.10 (m, 1I H), 6.54 (d, 1H), 5.50 (d, 1H),4.05 (d, 2H), 3.71 (s, 3H) 3.10 (m, 4H), 2.90 (m, 2H). m/z: [M+H⁺] calcdfor C₃₃H₃₄N₄O₄ 551.27; found 551.4.

[0762] The intermediate compound3-(3-aminomethylphenyl)-4-methoxyaniline was prepared as follows:

[0763] a. Synthesis of 2-(3-aminomethylphenyl)-4-nitroanisole

[0764] 2-(3-cyanophenyl)-4-nitroanisole (8.0 g) from Example 111, parta, was dissolved in THF (200 mL) and purged with nitrogen. A 11.0Msolution of borane in THF (135 mL) was then added, and the reaction washeated at reflux for 4 hours. When the reaction was complete, themixture was cooled to room temperature and 4.0N HCl in dioxane (25 mL)was added dropwise over 30 minutes. Methanol (200 mL) was slowly addedto the acidified solution, and the solvent was removed in vacuo. Theresulting gum was redissolved in methanol(150 mL) and concentrated invacuo to give a solid. The product was dissolved in dichloromethane (150mL) and cooled to −20° C. to give 2-(3-aminomethylphenyl)-4-nitroanisolewhich was collected on a filter and dried in vacuo.

[0765] b. Synthesis of 3-(3-aminomethylphenyl)-4-methoxyaniline

[0766] To a solution of 2-(3-aminomethylphenyl)-4-nitroanisole (5.88 g)in methanol (100 mL) was added 10% palladium on carbon (3.9 g). Thereaction mixture was stirred under one atmosphere of hydrogen for 12hours. The catalyst was removed by filtration and the solvent wasremoved in vacuo. The residue was partitioned between 1N NaOH anddichloromethane. The organic layer was dried over Na₂SO₄ andconcentrated. The resulting oil was dissolved in dichloromethane (50 mL)and 4.0N HCl in dioxane was added. The product was collected byfiltration and dried in vacuo to give the HCl salt of3-(3-aminomethylphenyl)-4-methoxyaniline as an off white powder. ¹H NMR(300 MHz, DMSO-d₆) δ 8.46 (m, 2H), 7.33-7.49 (m, 4H), 6.80 (d, J=7.9 Hz,1H), 6.58-6.61 (m, 2H), 5.82 (br s, 2H), 3.95 (m, 2H), 3.54 (s, 3H)

Example 113 Synthesis ofN-{2-[4-(3-(3-(N-isopropylamino)methylphenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine(113)

[0767] Compound 113: Formula (XI) where R¹¹ is3-(N-isopropylamino)methylphenyl

[0768] Using procedures similar to those described in Example 61C andthe deprotection step of Example 61B, except replacing the4-methoxy-3-phenylaniline hydrochloride with3-[3-(N-isopropylamino)methylphenyl]-4-methoxyaniline in Example 61C,part d, compound 113 was prepared. m/z: [M+H⁺] calcd for C₃₆H₄₁N₄O₄593.31; found 593.4.

[0769] The intermediate compound3-[3-(N-isopropylamino)methylphenyl]-4-methoxyaniline was prepared asfollows:

[0770] a. Synthesis of2-(3-(N-isopropylamino)methylphenyl)-4-nitroanisole

[0771] 2-(3-Aminomethylphenyl)-4-nitroanisole (0.10 g, 0.39 mmol) wasdissolved in anhydrous acetone (25 mL). The solution was distilled atatmospheric pressure until the volume was reduced to approximately 5 mL.The solution was then distilled under reduced pressure at roomtemperature to remove the last traces of acetone. The resultant oil wasre-dissolved in CH₂Cl₂/MeOH (2 mL:1 mL). Sodium borohydride (44 mg, 3equiv) was added, and the reaction mixture stirred at room temperaturefor 2 h. The solution was then diluted with CH₂Cl₂ (10 mL), extractedwith 1M NaOH (4×5 mL), dried (Na₂SO₄), and evaporated to afford2-(3-(N-isopropylamino)methylphenyl)-4-nitroanisole (120 mg, 0.39 mmol,100%).

[0772] b. Synthesis of3-[3-(N-isopropylamino)methylphenyl]-4-methoxyaniline

[0773] 2-(3-(N-Isopropylamino)methylphenyl)-4-nitroanisole (120 mg, 0.39mmol) was dissolved in MeOH/THF (5 mL:5 mL), and 10% Pd/C (20 mg) wasadded. The slurry was stirred at room temperature under an atmosphere ofH₂ for 16 h. The slurry was then filtered and evaporated to afford3-[3-(N-isopropylamino)methylphenyl]-4-methoxyaniline as a brown oil(101 mg, 0.37 mmol, 96%).

Example 114 Synthesis ofN-{2-[4-(3-(3-(N-benzylamino)methylphenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine(114)

[0774] Compound 114: Formula (XI) where R¹¹ is3-(N-benzylamino)methylphenyl

[0775]N-{2-[4-(3-(3-(N-benzylamino)methylphenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-tert-butyldimethylsilyloxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine(55 mg, 0.73 mmol) was dissolved in THF/MeOH (5 mL:2 mL).Triethylamine-trihydrofluoride (0.5 mL) was added, and the reactionmixture was stirred at room temperature for 5 h. The solvent was thenevaporated, and the residue purified by HPLC to affordN-{2-[4-(3-(3-(N-benzylamino)methylphenyl)-4-methoxyphenyl)aminophenyl]ethyl—(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine (114).m/z:[M+H⁺] calcd for C₄₀H₄₁N₄O₄ 641.31; found 641.3

[0776] The intermediateN-{2-[4-(3-(3-(N-benzylamino)methylphenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-tert-butyldimethylsilyloxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylaminewas prepared as follows:

[0777] a. Synthesis of 2-(3-aminomethylphenyl)-4-nitroanisoleHydrochloride

[0778] To a stirring solution of 2-(3-cyanophenyl)-4-nitroanisole fromExample 111 (4.0 g, 16 mmol) in tetrahydrofuran (100 mL) was addedboranetetrahydrofuran complex dropwise (48 mL of a 1.0 M solution intetrahydrofuran, 3 equiv, 48 mmol). The solution was heated to refluxfor 3 hours. The solution was allowed to cool to room temperature andhydrochloride acid (24 mL of 4.0 M solution in dioxane, 96 mmol) wasadded slowly. Methanol (100 mL) was added slowly and the solution wasevaporated to dryness. The residue was diluted with methanol (100 mL)and evaporated to dryness. The residue was dissolved in dichloromethane(100 mL). A clear solution was achieved, from which a precipitate beganto form (<1 min). The solution was stirred at room temperature for 14hours and the solid was collected on a Büchner funnel, washed withdichloromethane (10 mL), and dried under high vacuum to afford2-(3-aminomethylphenyl)-4-nitroanisole hydrochloride (2.26 g, 55%yield).

[0779] b. Synthesis of 3-(3-aminomethylphenyl)-4-methoxyanilineDihydrochloride

[0780] To a solution of 2-(3-aminomethylphenyl)-4-nitroanisolehydrochloride (1.26 g, 4.2 mmol) in methanol (10 mL) and tetrahydrofuran(10 mL) under nitrogen was added palladium on carbon (10% by weight, 200mgs, 15 wt. %). The solution was purged with hydrogen and stirred underhydrogen for 24 hours. The reaction was purged with nitrogen and thecatalyst was removed by filtration. Solvent was removed in vacuo and theresidue was redissolved in dichloromethane (10 mL) and hydrochlorideacid was added (4.0 M solution in dioxane, 1.5 equiv., 1.57 mL). Thesolution was stirred for 1 hour while a solid precipitated. The solidwas collected on a Buchner funnel and dried under vacuum to afford3-(3-aminomethylphenyl)-4-methoxyaniline dihydrochloride (947 mgs, 73%yield).

[0781] c. Synthesis ofN-{2-[4-(3-(3-aminomethylphenyl)-4-methoxy)aminophenyl]ethyl}-(R)-2-tert-butyldimethylsilyloxy-2-(8-benzyloxy-2(1H)-quinolinon-5-yl)ethylamine

[0782] Using procedures similar to those described in Example 61C,except replacing the 4-methoxy-3-phenylaniline hydrochloride with3-(3-aminomethylphenyl)-4-methoxyaniline in Example 61C, part d,N-{2-[4-(3-(3-aminomethylphenyl)-4-methoxy)aminophenyl]ethyl}-(R)-2-tert-butyldimethylsilyloxy-2-(8-benzyloxy-2(1H)-quinolinon-5-yl)ethylaminewas prepared.

[0783] d. Synthesis ofN-{2-[4-(3-(3-aminomethylphenyl)-4-methoxy)aminophenyl]ethyl}-(R)-2-tert-butyldimethylsilyloxy-2-(8-hydroxy-2(H1T)-quinolinon-5-yl)ethyl amine

[0784]N-{2-[4-(3-(3-aminomethylphenyl)-4-methoxy)aminophenyl]ethyl}-(R)-2-tert-butyldimethylsilyloxy-2-(8-benzyloxy-2(1H)-quinolinon-5-yl)ethylamine(140 mg, 0.19 mmol) was dissolved in EtOH (5 mL). Palladium hydroxide(20% w/w on carbon, 20 mg) was added, and the slurry was stirred at roomtemperature under an atmosphere of H₂ for 16 h. The reaction mixture wasfiltered and the filtrate evaporated to affordN-{2-[4-(3-(3-aminomethylphenyl)-4-methoxy)aminophenyl]ethyl}-(R)-2-tert-butyldimethylsilyloxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine

[0785] e. Synthesis ofN-{2-[4-(3-(3-(N-benzylamino)methylphenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-tert-butyldimethylsilyloxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine

[0786]N-{2-[4-(3-(3-aminomethylphenyl)-4-methoxy)aminophenyl]ethyl}-(R)-2-tert-butyldimethylsilyloxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine(27.5 mg, 0.41 mmol) and benzaldehyde (4.2 μL, 1 equiv) were dissolvedin anhydrous MeOH (2 mL) and stirred at room temperature for 2.5 h.Sodium borohydride (9.4 mg, 6 equiv) was added, and the reaction mixturewas stirred at rt for 48 h. The solution was then diluted with EtOAc (50mL), washed with H₂O (30 mL), dried (Na₂SO₄), and evaporated to affordN-{2-[4-(3-(3-(N-benzylamino)methylphenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-tert-butyldimethylsilyloxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine(26 mg, 0.34 mmol, 83%)

Example 115 Synthesis ofN-{2-[4-(3-(3-(N,N-dimethylamino)methylphenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine(115)

[0787] Compound 115: Formula (XI) where R¹¹ is3-(N,N-dimethylamino)methylphenyl.

[0788] Using procedures similar to those described in Example 61C andthe deprotection step of Example 61B, except replacing the4-methoxy-3-phenylaniline hydrochloride with3-[3-(N,N-dimethylamino)methylphenyl]-4-methoxyaniline in Example 61C,part d, compound 115 was prepared. m/z: [M+H⁺] calcd for C₃₅H₃₉N₄O₄,579.30; found 579.3 The intermediate compound3-[3-(N,N-dimethylamino)methylphenyl]-4-methoxyaniline was prepared asfollows:

[0789] a. Synthesis of2-(3-(N,N-dimethylamino)methylphenyl)-4-nitroanisole

[0790] 2-(3-Aminomethylphenyl)-4-nitroanisole (0.21 g, 0.81 mmol) wasdissolved in a mixture of formic acid (12 mL) and 37% aqueousformaldehyde (6 mL). The solution was then refluxed for 16 h. Thereaction mixture was diluted with 1M NaOH (10 mL) and extracted withCH₂Cl₂ (2×10 mL). The combined organic phases were filtered, dried(Na₂SO4) and evaporated to afford2-(3-(N,N-dimethylamino)methylphenyl)-4-nitroanisole (200 mg, 0.70 mmol,86%)

[0791] b. Synthesis of3-[3-(N,N-dimethylamino)methylphenyl]-4-methoxyaniline

[0792] 2-(3-(N,N-Dimethylamino)methylphenyl)-4-nitroanisole (200 mg,0.70 mmol) was dissolved in EtOH/H₂O (5 mL:2.5 mL). concentrated HCl (40uL) was added, followed by iron powder (314 mg). The reaction mixturewas refluxed for 1 h, allowed to cool to room temperature, and dilutedwith EtOH (10 mL). The slurry was filtered and the filtrate evaporated.The resultant oil was taken up in 1 M NaOH (10 mL) and extracted withCH₂Cl₂ (2×10 mL). The combined organic phases were dried (Na₂SO₄) andevaporated to afford3-[3-(N,N-dimethylamino)methylphenyl]-4-methoxyaniline as a brown oil(102 mg, 0.40 mmol, 57%)

Example 116 Synthesis ofN-{2-[4-(3-(3-(N-(3-pyridylmethyl)aminomethyl)phenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine(116)

[0793] Compound 116: Formula (XI) where R¹¹ is3-[N-(3-pyridylmethyl)aminomethyl]phenyl.

[0794] Using procedures described in Example 114, part e, except usingpyridine-3-carboxaldehyde in place of benzaldehyde,N-{2-[4-(3-(3-(N-(3-pyridylmethyl)aminomethyl)phenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylaminewas synthesized. m/z: [M+H⁺] calcd for C₃₉H₄₀N₅O₄ 642.31; found 642.4

Example 117 Synthesis ofN-{2-[4-(3-(3-(N-(4-methoxybenzylamino))methylphenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine(117)

[0795] Compound 117: Formula (XI) where R¹¹ is3-(N-(4-methoxybenzylamino))methylphenyl.

[0796] Using procedures described in Example 114 part e, except using4-methoxybenzaldehyde in place of benzaldehyde,N-{2-[4-(3-(3-(N-(4-methoxybenzylamino))methylphenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylaminewas synthesized. m/z: [M+H⁺] calcd for C₄₁H₄₃N₄O₅ 671.32; found 671.5

Example 118 Synthesis ofN-{2-[4-(3-(4-aminomethylphenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine(96)

[0797] Using procedures similar to those described in Example 61 C andthe deprotection step of Example 61B, except replacing the4-methoxy-3-phenylaniline hydrochloride with3-(4-aminomethylphenyl)-4-methoxyaniline in Example 61C, part d,compound 96 was prepared.

[0798] The intermediate compound3-(4-aminomethylphenyl)-4-methoxyaniline was prepared as follows:

[0799] a. Synthesis of 2-(4-aminomethylphenyl)-4-nitroanisole

[0800] A mixture of 2-bromo-4-nitroanisole (5.80 g, 25.0 mmol) and4-(aminomethyl)phenylboronic acid hydrochloride (4.96 g, 26.6 mmol) wasslurried in 1-propanol (50 mL) under nitrogen. Triphenylphosphine (315mg, 1.20 mmol) and palladium (II) acetate (90 mg, 0.40 mmol) were added,followed by 2.0N sodium carabonate(33 mL, 66 mmol). The mixture washeated at 95° C. (oil bath) under nitrogen for 3 hours, at which timethe reaction was judged to be complete by TLC. Water (25 mL) was addedand the mixture was stirred open to air for 2 hours at room temperature.The mixture was extracted with ethyl acetate (100 mL, 2×50 mL) and thecombined extracts were washed with sodium bicarbonate (25 mL) and brine(25 mL). The solution was dried with sodium sulfate, and concentrated toan oil which was purified by flash chromatography on silica gel (100 g)eluting with 0-4% methanol/0,5% triethylamine/dichloromethane. Purefractions were combined and concentrated to give2-(4-aminomethylphenyl)-4-nitroanisole (4.6 g) as a yellow solid.

[0801] b. Synthesis of 3-(4-aminomethylphenyl)-4-methoxyaniline

[0802] A solution of 2-(4-aminomethylphenyl)-4-nitroanisole (4.50 g) inmethanol (200 mL) was treated with 10% palladium on carbon (200 mg). Thereaction mixture was stirred under one atmosphere of hydrogen for 2.5hours. The reaction mixture filtered through Celite, and the filter cakewas washed with methanol (3×25 mL). The filtrate was concentrated todryness and the residue was purified by flash chromatography on silicagel (80 g) eluting with 0-6% methanol/0.5%triethylamine/dichloromethane. Pure fractions were combined andconcentrated to give 3-(4-aminomethylphenyl)-4-methoxyaniline as an offwhite powder.

Example 119 Synthesis ofN-{2-[4-(3-(3-chlorophenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine(102)

[0803] Using procedures similar to those described in Example 61C andthe deprotection step of Example 61B, except replacing the4-methoxy-3-phenylaniline hydrochloride with3-(3-chlorophenyl)-4-methoxyaniline in Example 61C, part d, compound 102was prepared.

[0804] The intermediate compound 3-(3-chlorophenyl)-4-methoxyaniline wasprepared as follows:

[0805] a. Synthesis of 2-(3-chlorophenyl)-4-nitroanisole

[0806] To a flask containing a bi-phasic mixture of2-bromo-4-nitroanisole (15.0 g, 64.6 mmol) and 3-chlorophenylboronicacid (12.1 g, 77.6 mmol) in ethylene glycol dimethyl ether (187.5 mL)and 2.0 N aqueous cesium carbonate (97 mL) was added1-1′-bis(diphenylphosphino)ferrocene)dichloro palladium (II), complexwith dichloromethane (1:1) (1.5 g). The mixture was heated at reflux for4 hours under a nitrogen atmosphere. The crude reaction mixture waspartitioned between ethyl acetate (350 mL) and brine (250 mL) and thenfiltered through a Buchner funnel. Layers were separated and the organiclayer was washed with brine (250 mL). The organic phase was dried overNa₂SO₄, filtered, and concentrated to a dark oil. The crude residue waspurified by flash chromatography on silica gel using dichloromethane asthe eluent to afford 2-(3-chlorophenyl)-4-nitroanisole as a yellow solid(13.9 g, 59.4 mmol).

[0807] b. Synthesis of 3-(3-chlorophenyl)-4-methoxyaniline

[0808] To a mixture of 2-(3-chlorophenyl)-4-nitroanisole (0.5 g, 1.9mmol)in tetrahydrofuran (5 mL) and methanol (5 mL) was added platinum(IV) oxide (1 mg). The reaction was stirred at room temperature underone atmosphere of hydrogen for 4.5 hours. The slurry was filteredthrough Celite and concentrated under reduced pressure to afford3-(3-chlorophenyl)-4-methoxyaniline as a light yellow oil (405 mg, 1.7mmol).

[0809] While the present invention has been described with reference tothe specific embodiments thereof, it should be understood by thoseskilled in the art that various changes may be made and equivalents maybe substituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective, spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto. Additionally, all publications, patents, andpatent documents cited hereinabove are incorporated by reference hereinin full, as though individually incorporated by reference.

What is claimed is:
 1. A combination comprising a compound of formula(I):

wherein: each of R¹-R⁵ is independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,cycloalkyl, heterocyclyl, and R^(a); or R¹ and R², R² and R³, R³ and R⁴,or R⁴ and R⁵ are joined together to form a group selected from the groupconsisting of —C(R^(d))═C(R^(d))C(═O)NR^(d)—,—CR^(d)R^(d)—CR^(d)R^(d)—C(═O)NR^(d)—, —NR^(d)C(═O)C(R^(d))═C(R^(d))—,—NR^(d)C(═O)CR^(d)R^(d)—CR^(d)R^(d)—, —NR^(d)C(═O)S—, —SC(═O)NR^(d)—,—(CR^(d)R^(d))_(p)—, —S(CR^(d)R^(d))_(q)—, —(CR^(d)R^(d))_(q)S—,—S(CR^(d)R^(d))_(r)O—, —O(CR^(d)R^(d))_(r)S—, and —NHC(R^(j))═C(R^(k))—;R⁶ is hydrogen, alkyl, or alkoxy; R⁷ is hydrogen or alkyl; R⁸ ishydrogen or alkyl; or R⁸ together with R⁹ is —CH₂— or —CH₂CH₂—; R⁹ isindependently selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, and R^(a), or R⁹together with R⁸ is —CH₂— or —CH₂CH₂—; R¹⁰ is hydrogen or alkyl; eachR¹¹, R¹², and R¹³ is independently selected from the group consisting ofhydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl, —NO₂, halo, —NR^(d)R^(e), —C(═O)R^(d), —CO₂R^(d),—OC(═O)R^(d), —CN, —C(═O)NR^(d)R^(e), —NR^(d)C(═O)R^(e),—OC(═O)NR^(d)R^(e), —NR^(d)C(═O)OR^(e), —NR^(d)C(═O)NR^(d)R^(e),—OR^(d), —S(O)_(m)R^(d), —NR^(d)—NR^(d)—C(═O)R^(d),—NR^(d)N═CR^(d)R^(d), —N(NR^(d)R^(e))R^(d), and —S(O)₂NR^(d)R^(e); orR¹¹ and R¹² together with the atoms to which they are attached form afused benzo ring, which benzo ring can optionally be substituted with 1,2, 3, or 4 R^(e); or R¹¹ and R¹² together with the atoms to which theyare attached form a heterocyclic ring; wherein for R¹-R⁶, R⁹, andR¹¹-R¹³, each alkyl, alkenyl, and alkynyl is optionally substituted withR^(m), or with 1, 2, 3, or 4 substituents independently selected fromR^(b); for R¹-R⁶, R⁹, and R¹¹-R¹³, each aryl and heteroaryl isoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(c), and for R¹-R⁶, R⁹, and R¹¹-R¹³ each cycloalkyl andheterocyclyl is optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(b) and R^(e); each R^(a) is independently—OR^(d), —NO₂, halo, —S(O)_(m)R^(d), —S(O)₂OR^(d), —S(O)_(m)NR^(d)R^(e),—NR^(d)R^(e), —O(CR^(f)R^(g))_(n)NR^(d)R^(e), —C(═O)R^(d), CO₂R^(d),—CO₂(CR^(f)R^(g))_(n)CONR^(d)R^(e), —OC(═O)R^(d), —CN,—C(═O)NR^(d)R^(e), —NR^(d)C(═O)R^(c), —OC(═O)NR^(d)R^(e),—NR^(d)C(═O)OR^(e), —NR^(d)C(═O)NR^(d)R^(e), —CR^(d)(═N—OR^(c)), —CF₃,or —OCF₃; each R^(b) is independently R^(a), oxo, or ═N—OR^(e); eachR^(c) is independently R^(a), alkyl, alkenyl, or alkynyl; wherein eachalkyl, alkenyl and alkynyl is optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(b); each R^(d) and R^(e) isindependently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,cycloalkyl, or heterocyclyl; wherein each alkyl, alkenyl, alkynyl, aryl,heteroaryl, cycloalkyl and heterocyclyl is optionally substituted with1, 2, 3, or 4 substituents independently selected from R^(b); or R^(d)and R^(e) together with the atoms to which they are attached form aheterocyclic ring having from 5 to 7 ring atoms, wherein theheterocyclic ring optionally contains 1 or 2 additional heteroatomsindependently selected from oxygen, sulfur or nitrogen; each R^(f) andR^(g) is independently hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, orheterocyclyl; wherein each alkyl, aryl, heteroaryl, cycloalkyl andheterocyclyl is optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(b); or R^(f) and R^(g) together with thecarbon atom to which they are attached form a ring having from 5 to 7ring atoms, wherein the ring optionally contains 1 or 2 heteroatomsindependently selected from oxygen, sulfur or nitrogen; each R^(h) isindependently halo, C₁₋₈alkyl, C₁₋₈alkoxy, —S—C₁₋₈alkyl, aryl,(aryl)-C₁₋₆alkyl, (aryl)-C₁₋₈alkoxy, heteroaryl, (heteroaryl)-C₁₋₆alkyl,(heteroaryl)-C₁₋₈alkoxy, hydroxy, amino, —NHC₁₋₆alkyl, —N(C₁₋₆alkyl)₂,—OC(═O)C₁₋₆alkyl, —C(═O)C₁₋₆alkyl, —C(═O)OC₁₋₆alkyl, —NHC(═O)C₁₋₆alkyl,—C(═O)NHC₁₋₆alkyl, carboxy, nitro, —CN, or —CF₃; R^(j) and R^(k)together with the carbon atoms to which they are attached form a phenylring that is optionally substituted with 1, 2, 3, or 4 R^(c); each R^(m)is independently aryl, heteroaryl, cycloalkyl or heterocyclyl; whereineach aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4substituents selected from the group consisting of RC, and wherein eachcycloalkyl and heterocyclyl is optionally substituted with 1, 2, 3, or 4substituents selected from R^(b); m is 0, 1, or 2; n is 0, 1, 2, 3, 4,5, 6, 7, 8, 9, or 10; p is 3, 4, or 5; q is 2, 3, or 4; r is 1, 2, or 3;and w is 0, 1, 2, 3, or 4; or a pharmaceutically-acceptable salt orsolvate or stereoisomer thereof; and a corticosteroid selected from thegroup consisting of6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-[(4-methyl-1,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester and 6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester.
 2. The combination of claim 1 wherein R⁶, R⁸,and R¹⁰ are each hydrogen; and w is 0, 1, or
 2. 3. The combination ofclaim 1 wherein each of R¹-R⁴ is independently selected from the groupconsisting of hydrogen, fluoro, chloro, amino, hydroxy,N,N-dimethylaminocarbonyloxy, —CH₂OH, and —NHCHO, and R⁵ is hydrogen; orR¹ is hydrogen, R² is hydrogen, R³ is hydroxy, and R⁴ and R⁵ togetherare —NHC(═O)CH═CH— or —SC(═O)NH—.
 4. The combination of claim 1 whereineach of R¹-R⁵ is independently selected from the group consisting ofhydrogen, alkyl, and R^(a); wherein each R^(a) is independently —OR^(d),halo, —NR^(d)R^(e), —NR^(d)C(═O)RC, or —OC(═O)NR^(d)R^(e); or R¹ and R²,or R⁴ and R⁵, are joined together to form a group selected from thegroup consisting of —C(R^(d))═C(R^(d))C(═O)NR^(d)—,—CR^(d)R^(d)—CR^(d)R^(d)—C(═O)NR^(d)—, —NR^(d)C(═O)C(R^(d))═C(R^(d))—,—NR^(d)C(═O)CR^(d)R^(d)—CR^(d)R^(d)—, —NR^(d)C(═O)S—, and—SC(═O)NR^(d)—; R⁶, R⁸, and R¹⁰ are each hydrogen; each of R¹¹ and R¹²is independently selected from the group consisting of hydrogen, alkyl,cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, —NO₂,halo, —NR^(d)R^(e), —CO₂R^(d), —OC(═O)R^(d), —CN, —C(═O)NR^(d)R^(e),—NR^(d)C(═O)R^(e), —OR^(d), —S(O)_(m)R^(d), —NR^(d)—NR^(d)—C(═O)R^(d),—NR^(d)—N═CR^(d)R^(d), N(NR^(d)R^(e))R^(d), and —S(O)₂NR^(d)R^(e);wherein for R¹-R⁵, R¹¹, and R¹², each alkyl is optionally substitutedwith R^(m), or with 1, 2, 3, or 4 substituents independently selectedfrom R^(b); for R¹¹ and R¹², each aryl and heteroaryl is optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(c), and for R¹¹ and R¹², each cycloalkyl and heterocyclyl isoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(b) and R^(c); R¹³ is hydrogen; the group comprising—NR¹⁰ is meta or para to the group comprising R⁷; and w is 0, 1, or 2.5. The combination of claim 4 wherein each of R¹¹ and R¹² isindependently selected from the group consisting of hydrogen, alkyl,cycloalkyl, aryl, heterocyclyl, —OR^(d), —S(O)_(m)R^(d), and—S(O)₂NR^(d)R^(e); wherein each alkyl is optionally substituted with 1or 2 substituents independently selected from R^(b), each aryl isoptionally substituted with 1 or 2 substituents independently selectedfrom R^(c), and each heterocyclyl is optionally substituted with 1 or 2substituents independently selected from R^(b) and R^(c); and m is 0 or2.
 6. A combination of a compound of formula (IIa):

wherein: R⁴ is —CH₂OH or —NHCHO and R⁵ is hydrogen; or R⁴ and R⁵ takentogether are —NHC(═O)CH═CH—; R¹¹ is phenyl or heteroaryl, wherein eachphenyl is optionally substituted with 1 or 2 substituents selected fromhalo, —OR^(d), —CN, —NO₂, —SO₂R^(d), —C(═O)R^(d), —C(═O)NR^(d)R^(e), andC₁₋₃alkyl, wherein C₁₋₃alkyl is optionally substituted with 1 or 2substituents selected from carboxy, hydroxy, and amino, and each R^(d)and R^(e) is independently hydrogen or C₁₋₃alkyl; and wherein eachheteroaryl is optionally substituted with 1 or 2 C₁₋₃alkyl substituents;and R¹² is hydrogen or —OC₁₋₆alkyl; or a pharmaceutically-acceptablesalt or solvate or stereoisomer thereof; and a corticosteroid selectedfrom the group consisting of6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-[(4-methyl-1,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester and6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester.
 7. The combination of claim 6 wherein R¹¹ isphenyl, optionally substituted with 1 substituent selected from halo,—OR^(d), —CN, —NO₂, —SO₂R^(d), C(═O)R^(d), and C₁₋₃alkyl, whereinC₁₋₃alkyl is optionally substituted with 1 or 2 substituents selectedfrom carboxy, hydroxy, and amino, and R^(d) is hydrogen or C₁₋₃alkyl. 8.The combination of claim 6 wherein R¹¹ is pyridyl, thiophenyl, furanyl,pyrrolyl, isoxazolyl, or indolyl, each of which is optionallysubstituted with 1 or 2 C₁₋₃alkyl substituents.
 9. The combination ofclaim 6 wherein R¹¹ is phenyl, pyridyl, or thiophenyl, wherein eachphenyl is optionally substituted with 1 substituent selected from thegroup consisting of chloro, —OCH₃, —CN, and —CH₂NH₂; and R¹² ishydrogen, —OCH₃, or —OC₂H₅.
 10. The combination of claim 9 wherein R⁴and R⁵ taken together are —NHC(═O)CH═CH—; R¹¹ is phenyl or pyridyl,wherein each phenyl is optionally substituted with 1 substituentselected from the group consisting of chloro, —OCH₃, —CN, and —CH₂NH₂;and R¹² is —OCH₃.
 11. The combination of claim 6 wherein the compound offormula (IIa) is a mixture of stereosiomers wherein the amount of thestereoisomer having the (R) orientation at the chiral center to whichthe hydroxy group is attached is greater than the amount of thestereoisomer having the (S) orientation at the chiral center to whichthe hydroxy group is attached.
 12. The combination of claim 6 whereinthe compound of formula (IIa) is the stereoisomer having the (R)orientation at the chiral center to which the hydroxy group is attached.13. The combination of claim 6 wherein the compound of formula (IIa) isselected from the group consisting of:N-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine;N-{2-[4-(4-ethoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine;N-{2-[4-(3-phenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine;N-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;N-{2-[4-(4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine;N-{2-[4-(3-phenyl-4-ethoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine;N-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine;N-{2-[4-(4-ethoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine;N-{2-[4-(3-phenylphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine;N-{2-[4-(3-phenyl-4-ethoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine;N-{2-[4-(4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine;N-{2-[4-(4-ethoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;N-{2-[4-(3-phenylphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;N-{2-[4-(3-phenyl-4-ethoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;N-{2-[4-(4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;N-{2-[4-(3-(2-chlorophenyl)phenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;N-{2-[4-(3-(2-methoxyphenyl)phenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;N-{2-[4-(3-(3-cyanophenyl)phenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;N-{2-[4-(3-(4-aminomethylphenyl)phenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;N-{2-[4-(3-(3-chlorophenyl)phenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;N-{2-[4-(3-(4-aminomethylphenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;N-{2-[4-(3-(3-cyanophenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;N-{2-[4-(3-(4-hydroxyphenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;N-{2-[4-(3-(3-pyridyl)phenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;N-{2-[4-(3-(3-pyridyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;N-{2-[4-(3-(4-pyridyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;N-{2-[4-(3-(thiophen-3-yl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;andN-{2-[4-(3-(3-chlorophenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;N-{2-[4-(3-(3-aminomethylphenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;and pharmaceutically-acceptable salts or solvates thereof.
 14. Thecombination of claim 6 wherein the compound of formula (1Ha) is selectedfrom the group consisting of:N-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;N-{2-[4-(3-(4-aminomethylphenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;N-{2-[4-(3-(3-cyanophenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;N-{2-[4-(3-(3-chlorophenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;N-{2-[4-(3-(3-aminomethylphenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;and pharmaceutically-acceptable salts or solvates thereof.
 15. Thecombination of claim 14 wherein the corticosteroid is6(x,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester.
 16. A pharmaceutical composition comprising atherapeutically effective amount of a combination of claim 1 and apharmaceutically-acceptable carrier.
 17. The pharmaceutical compositionof claim 16, wherein the composition is formulated for administration byinhalation.
 18. A pharmaceutical composition comprising atherapeutically effective amount of a combination of claim 6 and apharmaceutically-acceptable carrier.
 19. The pharmaceutical compositionof claim 18, wherein the composition is formulated for administration byinhalation.
 20. A method of treating a disease or condition in a mammalassociated with β₂ adrenergic receptor activity, the method comprisingadministering to the mammal, a therapeutically effective amount of apharmaceutical composition comprising a combination of claim 1 and apharmaceutically-acceptable carrier.
 21. The method of claim 20 whereinthe disease or condition is a pulmonary disease.
 22. The method of claim21 wherein the pulmonary disease is asthma or chronic obstructivepulmonary disease.
 23. A method of treating a disease or condition in amammal associated with β₂ adrenergic receptor activity, the methodcomprising administering to the mammal, a therapeutically effectiveamount of a pharmaceutical composition comprising a combination of claim6 and a pharmaceutically-acceptable carrier.
 24. The method of claim 23wherein the disease or condition is a pulmonary disease.
 25. The methodof claim 24 wherein the pulmonary disease is asthma or chronicobstructive pulmonary disease.